Cycloalkyl-hydroxyl compounds and compositions for cholesterol management

ABSTRACT

The present invention relates to novel cycloalkyl-hydroxyl compounds, compositions comprising hydroxyl compounds, and methods useful for treating and preventing a variety of diseases and conditions such as, but not limited to aging, Alzheimer&#39;s Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, Parkinson&#39;s disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder. Compounds and methods of the invention can also be used to modulate C reactive protein or enhance bile production in a patient. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.12/135,504, filed Jun. 9, 2008, now allowed; which is a continuation ofU.S. Ser. No. 11/426,380, filed Jun. 26, 2006, now U.S. Pat. No.7,405,226; which is a divisional of U.S. Ser. No. 10/743,287, filed Dec.23, 2003, now U.S. Pat. No. 7,119,221; which claims benefit of U.S.Provisional Ser. No. 60/441,795, filed Jan. 23, 2003, all of which areincorporated herein by reference in their entirety.

1. FIELD OF THE INVENTION

The invention relates to cycloalkyl-hydroxyl compounds andpharmaceutically acceptable salts, hydrates, solvates, and mixturesthereof; compositions comprising a hydroxyl compound or apharmaceutically acceptable salt, hydrate, solvate, or mixtures thereof;and methods for treating or preventing a disease or disorder such as,but not limited to, aging, Alzheimer's Disease, cancer, cardiovasculardisease, diabetic nephropathy, diabetic retinopathy, a disorder ofglucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bileproduction, enhancing reverse lipid transport, hypertension, impotence,inflammation, insulin resistance, lipid elimination in bile, modulatingC reactive protein, obesity, oxysterol elimination in bile,pancreatitis, Parkinson's disease, a peroxisome proliferator activatedreceptor-associated disorder, phospholipid elimination in bile, renaldisease, septicemia, metabolic syndrome disorders (e.g., Syndrome X),and a thrombotic disorder, which method comprise administering ahydroxyl compound or composition of the invention. The compounds of theinvention can also treat or prevent inflammatory processes and diseaseslike gastrointestinal disease, irritable bowel syndrome (IBS),inflammatory bowel disease (e.g., Crohn's Disease, ulcerative colitis),arthritis (e.g., rheumatoid arthritis, osteoarthritis), autoimmunedisease (e.g., systemic lupus erythematosus), scleroderma, ankylosingspondylitis, gout and pseudogout, muscle pain: polymyositis/polymyalgiarheumatica/fibrositis; infection and arthritis, juvenile rheumatoidarthritis, tendonitis, bursitis and other soft tissue rheumatism.

2. BACKGROUND OF THE INVENTION

Obesity, hyperlipidemia, and diabetes have been shown to play a causalrole in atherosclerotic cardiovascular diseases, which currently accountfor a considerable proportion of morbidity in Western society. Further,one human disease, termed “Syndrome X” or “Metabolic Syndrome”, ismanifested by defective glucose metabolism (insulin resistance),elevated blood pressure (hypertension), and a blood lipid imbalance(dyslipidemia). See e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131.

The evidence linking elevated serum cholesterol to coronary heartdisease is overwhelming. Circulating cholesterol is carried by plasmalipoproteins, which are particles of complex lipid and proteincomposition that transport lipids in the blood. Low density lipoprotein(LDL) and high density lipoprotein (HDL) are the majorcholesterol-carrier proteins. LDL is believed to be responsible for thedelivery of cholesterol from the liver, where it is synthesized orobtained from dietary sources, to extrahepatic tissues in the body. Theterm “reverse cholesterol transport” describes the transport ofcholesterol from extrahepatic tissues to the liver, where it iscatabolized and eliminated. It is believed that plasma HDL particlesplay a major role in the reverse transport process, acting as scavengersof tissue cholesterol. HDL is also responsible for the removal ofnon-cholesterol lipid, oxidized cholesterol and other oxidized productsfrom the bloodstream.

Atherosclerosis, for example, is a slowly progressive diseasecharacterized by the accumulation of cholesterol within the arterialwall. Compelling evidence supports the belief that lipids deposited inatherosclerotic lesions are derived primarily from plasma apolipoproteinB (apo B)-containing lipoproteins, which include chylomicrons, very lowdensity lipoproteins (VLDL), intermediate-density lipoproteins (IDL),and LDL. The apo B-containing lipoprotein, and in particular LDL, haspopularly become known as the “bad” cholesterol. In contrast, HDL serumlevels correlate inversely with coronary heart disease. Indeed, highserum levels of HDL are regarded as a negative risk factor. It ishypothesized that high levels of plasma HDL are not only protectiveagainst coronary artery disease, but may actually induce regression ofatherosclerotic plaque (e.g., see Badimon et al., 1992, Circulation86:(Suppl. III)86-94; Dansky and Fisher, 1999, Circulation 100:1762 3.).Thus, HDL has popularly become known as the “good” cholesterol.

2.1 Cholesterol Transport

The fat-transport system can be divided into two pathways: an exogenousone for cholesterol and triglycerides absorbed from the intestine and anendogenous one for cholesterol and triglycerides entering thebloodstream from the liver and other non-hepatic tissue.

In the exogenous pathway, dietary fats are packaged into lipoproteinparticles called chylomicrons, which enter the bloodstream and delivertheir triglycerides to adipose tissue for storage and to muscle foroxidation to supply energy. The remnant of the chylomicron, whichcontains cholesteryl esters, is removed from the circulation by aspecific receptor found only on liver cells. This cholesterol thenbecomes available again for cellular metabolism or for recycling toextrahepatic tissues as plasma lipoproteins.

In the endogenous pathway, the liver secretes a large, very-low-densitylipoprotein particle (VLDL) into the bloodstream. The core of VLDLconsists mostly of triglycerides synthesized in the liver, with asmaller amount of cholesteryl esters either synthesized in the liver orrecycled from chylomicrons. Two predominant proteins are displayed onthe surface of VLDL, apolipoprotein B-100 (apo B-100) and apolipoproteinE (apo E), although other apolipoproteins are present, such asapolipoprotein CIII (apo CIII) and apolipoprotein CII (apo CII). WhenVLDL reaches the capillaries of adipose tissue or of muscle, itstriglyceride is extracted. This results in the formation of a new kindof particle called intermediate-density lipoprotein (IDL) or VLDLremnant, decreased in size and enriched in cholesteryl esters relativeto a VLDL, but retaining its two apoproteins.

In human beings, about half of the IDL particles are removed from thecirculation quickly, generally within two to six hours of theirformation. This is because IDL particles bind tightly to liver cells,which extract IDL cholesterol to make new VLDL and bile acids. The IDLnot taken up by the liver is catabolized by the hepatic lipase, anenzyme bound to the proteoglycan on liver cells. Apo E dissociates fromIDL as it is transformed to LDL. Apo B-100 is the sole protein of LDL.

Primarily, the liver takes up and degrades circulating cholesterol tobile acids, which are the end products of cholesterol metabolism. Theuptake of cholesterol-containing particles is mediated by LDL receptors,which are present in high concentrations on hepatocytes. The LDLreceptor binds both apo E and apo B-100 and is responsible for bindingand removing both IDL and LDL from the circulation. In addition, remnantreceptors are responsible for clearing chylomicrons and VLDL remnants(i.e., IDL). However, the affinity of apo E for the LDL receptor isgreater than that of apo B-100. As a result, the LDL particles have amuch longer circulating life span than IDL particles; LDL circulates foran average of two and a half days before binding to the LDL receptors inthe liver and other tissues. High serum levels of LDL, the “bad”cholesterol, are positively associated with coronary heart disease. Forexample, in atherosclerosis, cholesterol derived from circulating LDLaccumulates in the walls of arteries. This accumulation forms bulkyplaques that inhibit the flow of blood until a clot eventually forms,obstructing an artery and causing a heart attack or stroke.

Ultimately, the amount of intracellular cholesterol liberated from theLDL controls cellular cholesterol metabolism. The accumulation ofcellular cholesterol derived from VLDL and LDL controls three processes.First, it reduces the ability of the cell to make its own cholesterol byturning off the synthesis of HMGCoA reductase, a key enzyme in thecholesterol biosynthetic pathway. Second, the incoming LDL-derivedcholesterol promotes storage of cholesterol by the action of cholesterolacyltransferase (“ACAT”), the cellular enzyme that converts cholesterolinto cholesteryl esters that are deposited in storage droplets. Third,the accumulation of cholesterol within the cell drives a feedbackmechanism that inhibits cellular synthesis of new LDL receptors. Cells,therefore, adjust their complement of LDL receptors so that enoughcholesterol is brought in to meet their metabolic needs, withoutoverloading (for a review, see Brown & Goldstein, in The PharmacologicalBasis Of Therapeutics, 8th Ed., Goodman & Gilman, Pergamon Press, NewYork, 1990, Ch. 36, pp. 874-896).

High levels of apo B-containing lipoproteins can be trapped in thesubendothelial space of an artery and undergo oxidation. The oxidizedlipoprotein is recognized by scavenger receptors on macrophages. Bindingof oxidized lipoprotein to the scavenger receptors can enrich themacrophages with cholesterol and cholesteryl esters independently of theLDL receptor. Macrophages can also produce cholesteryl esters by theaction of ACAT. LDL can also be complexed to a high molecular weightglycoprotein called apolipoprotein(a), also known as apo(a), through adisulfide bridge. The LDL-apo(a) complex is known as Lipoprotein(a) orLp(a). Elevated levels of Lp(a) are detrimental, having been associatedwith atherosclerosis, coronary heart disease, myocardial infarction,stroke, cerebral infarction, and restenosis following angioplasty.

2.2 Reverse Cholesterol Transport

Peripheral (non-hepatic) cells predominantly obtain their cholesterolfrom a combination of local synthesis and uptake of preformed sterolfrom VLDL and LDL. Cells expressing scavenger receptors, such asmacrophages and smooth muscle cells, can also obtain cholesterol fromoxidized apo B-containing lipoproteins. In contrast, reverse cholesteroltransport (RCT) is the pathway by which peripheral cell cholesterol canbe returned to the liver for recycling to extrahepatic tissues, hepaticstorage, or excretion into the intestine in bile. The RCT pathwayrepresents the only means of eliminating cholesterol from mostextrahepatic tissues and is crucial to the maintenance of the structureand function of most cells in the body.

The enzyme in blood involved in the RCT pathway, lecithin:cholesterolacyltransferase (LCAT), converts cell-derived cholesterol to cholesterylesters, which are sequestered in HDL destined for removal. LCAT isproduced mainly in the liver and circulates in plasma associated withthe HDL fraction. Cholesterol ester transfer protein (CETP) and anotherlipid transfer protein, phospholipid transfer protein (PLTP), contributeto further remodeling the circulating HDL population (see for exampleBruce et al., 1998, Annu. Rev. Nutr. 18:297 330). PLTP supplies lecithinto HDL, and CETP can move cholesteryl esters made by LCAT to otherlipoproteins, particularly apoB-containing lipoproteins, such as VLDL.HDL triglycerides can be catabolized by the extracellular hepatictriglyceride lipase, and lipoprotein cholesterol is removed by the livervia several mechanisms.

Each HDL particle contains at least one molecule, and usually two tofour molecules, of apolipoprotein A I (apo A I). Apo A I is synthesizedby the liver and small intestine as preproapolipoprotein, which issecreted as a proprotein that is rapidly cleaved to generate a maturepolypeptide having 243 amino acid residues. Apo A I consists mainly of a22 amino acid repeating segment, spaced with helix-breaking prolineresidues. Apo A I forms three types of stable structures with lipids:small, lipid-poor complexes referred to as pre-beta-1 HDL; flatteneddiscoidal particles, referred to as pre-beta-2 HDL, which contain onlypolar lipids (e.g., phospholipid and cholesterol); and sphericalparticles containing both polar and nonpolar lipids, referred to asspherical or mature HDL (HDL3 and HDL2). Most HDL in the circulatingpopulation contains both apo A I and apo A II, a second major HDLprotein. This apo A I- and apo A II-containing fraction is referred toherein as the AI/AII-HDL fraction of HDL. But the fraction of HDLcontaining only apo A I, referred to herein as the AI HDL fraction,appears to be more effective in RCT. Certain epidemiologic studiessupport the hypothesis that the AI-HDL fraction is antiartherogenic(Parra et al., 1992, Arterioscler. Thromb. 12:701-707; Decossin et al.,1997, Eur. J. Clin. Invest. 27:299-307).

Although the mechanism for cholesterol transfer from the cell surface isunknown, it is believed that the lipid-poor complex, pre-beta-1 HDL, isthe preferred acceptor for cholesterol transferred from peripheraltissue involved in RCT. Cholesterol newly transferred to pre-beta-1 HDLfrom the cell surface rapidly appears in the discoidal pre-beta-2 HDL.PLTP may increase the rate of disc formation (Lagrost et al., 1996, J.Biol. Chem. 271:19058-19065), but data indicating a role for PLTP in RCTis lacking. LCAT reacts preferentially with discoidal and spherical HDL,transferring the 2-acyl group of lecithin or phosphatidylethanolamine tothe free hydroxyl residue of fatty alcohols, particularly cholesterol,to generate cholesteryl esters (retained in the HDL) and lysolecithin.The LCAT reaction requires an apolipoprotein such as apo A I or apo A-IVas an activator. ApoA-I is one of the natural cofactors for LCAT. Theconversion of cholesterol to its HDL-sequestered ester prevents re-entryof cholesterol into the cell, resulting in the ultimate removal ofcellular cholesterol. Cholesteryl esters in the mature HDL particles ofthe AI-HDL fraction are removed by the liver and processed into bilemore effectively than those derived from the AI/AII-HDL fraction. Thismay be due, in part, to the more effective binding of AI-HDL to thehepatocyte membrane. Several HDL receptors have been identified, themost well characterized of which is the scavenger receptor class B, typeI (SR BI) (Acton et al., 1996, Science 271:518-520). The SR-BI isexpressed most abundantly in steroidogenic tissues (e.g., the adrenals),and in the liver (Landshulz et al., 1996, J. Clin. Invest. 98:984-995;Rigotti et al., 1996, J. Biol. Chem. 271:33545-33549). Other proposedHDL receptors include HB1 and HB2 (Hidaka and Fidge, 1992, Biochem J.15:161 7; Kurata et al., 1998, J. Atherosclerosis and Thrombosis 4:1127).

While there is a consensus that CETP is involved in the metabolism ofVLDL- and LDL-derived lipids, its role in RCT remains controversial.However, changes in CETP activity or its acceptors, VLDL and LDL, play arole in “remodeling” the HDL population. For example, in the absence ofCETP, the HDL becomes enlarged particles that are poorly removed fromthe circulation (for reviews on RCT and HDL, See Fielding & Fielding,1995, J. Lipid Res. 36:211-228; Barrans et al., 1996, Biochem. Biophys.Acta. 1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol.17:1053-1059).

2.3 Reverse Transport of Other Lipids

HDL is not only involved in the reverse transport of cholesterol, butalso plays a role in the reverse transport of other lipids, i.e., thetransport of lipids from cells, organs, and tissues to the liver forcatabolism and excretion. Such lipids include sphingomyelin, oxidizedlipids, and lysophophatidylcholine. For example, Robins and Fasulo(1997, J. Clin. Invest. 99:380 384) have shown that HDL stimulates thetransport of plant sterol by the liver into bile secretions.

2.4 Peroxisome Proliferator Activated Receptor Pathway

Peroxisome proliferators are a structurally diverse group of compoundsthat, when administered to rodents, elicit dramatic increases in thesize and number of hepatic and renal peroxisomes, as well as concomitantincreases in the capacity of peroxisomes to metabolize fatty acids viaincreased expression of the enzymes required for the β-oxidation cycle(Lazarow and Fujiki, 1985, Ann. Rev. Cell Biol. 1:489 530; Vamecq andDraye, 1989, Essays Biochem. 24:1115 225; and Nelali et al., 1988,Cancer Res. 48:5316 5324). Chemicals included in this group are thefibrate class of hypolipidemic drugs, herbicides, and phthalateplasticizers (Reddy and Lalwani, 1983, Crit. Rev. Toxicol. 12:1 58).Peroxisome proliferation can also be elicited by dietary orphysiological factors, such as a high fat diet and cold acclimatization.

Insight into the mechanism whereby peroxisome proliferators exert theirpleiotropic effects was provided by the identification of a member ofthe nuclear hormone receptor superfamily activated by these chemicals(Isseman and Green, 1990, Nature 347:645 650). This receptor, termedperoxisome proliferator activated receptor α (PPARα), was subsequentlyshown to be activated by a variety of medium and long chain fatty acids.PPARα activates transcription by binding to DNA sequence elements,termed peroxisome proliferator response elements (PPRE), in the form ofa heterodimer with the retinoid X receptor (RXR). RXR is activated by9-cis retinoic acid (see Kliewer et al., 1992, Nature 358:771 774;Gearing et al., 1993, Proc. Natl. Acad. Sci. USA 90:1440 1444, Keller etal., 1993, Proc. Natl. Acad. Sci. USA 90:2160 2164; Heyman et al., 1992,Cell 68:397 406, and Levin et al., 1992, Nature 355:359 361). Since thediscovery of PPARα, additional isoforms of PPAR have been identified,e.g., PPARβ, PPARγ and PPARδ, which have similar functions and aresimilarly regulated.

PPARs have been identified in the enhancers of a number of gene-encodingproteins that regulate lipid metabolism. These proteins include thethree enzymes required for peroxisomal β-oxidation of fatty acids;apolipoprotein A-I; medium chain acyl-CoA dehydrogenase, a key enzyme inmitochondrial β-oxidation; and aP2, a lipid binding protein expressedexclusively in adipocytes (reviewed in Keller and Whali, 1993, TEM,4:291 296; see also Staels and Auwerx, 1998, Atherosclerosis 137Suppl:S19 23). The nature of the PPAR target genes coupled with theactivation of PPARs by fatty acids and hypolipidemic drugs suggests aphysiological role for the PPARs in lipid homeostasis.

Pioglitazone, an antidiabetic compound of the thiazolidinedione class,was reported to stimulate expression of a chimeric gene containing theenhancer/promoter of the lipid binding protein aP2 upstream of thechloroamphenicol acetyl transferase reporter gene (Harris and Kletzien,1994, Mol. Pharmacol. 45:439 445). Deletion analysis led to theidentification of an approximately 30 bp region accounting forpioglitazone responsiveness. In an independent study, this 30 bpfragment was shown to contain a PPRE (Tontonoz et al., 1994, NucleicAcids Res. 22:5628 5634). Taken together, these studies suggested thepossibility that the thiazolidinediones modulate gene expression at thetranscriptional level through interactions with a PPAR and reinforce theconcept of the interrelatedness of glucose and lipid metabolism.

2.5 Current Cholesterol Management Therapies

In the past two decades or so, the segregation of cholesterolemiccompounds into HDL and LDL regulators and recognition of thedesirability of decreasing blood levels of the latter has led to thedevelopment of a number of drugs. However, many of these drugs haveundesirable side effects and/or are contraindicated in certain patients,particularly when administered in combination with other drugs.

Bile-acid-binding resins are a class of drugs that interrupt therecycling of bile acids from the intestine to the liver. Examples ofbile-acid-binding resins are cholestyramine (QUESTRAN LIGHT,Bristol-Myers Squibb), and colestipol hydrochloride (COLESTID, Pharmacia& Upjohn Company). When taken orally, these positively charged resinsbind to negatively charged bile acids in the intestine. Because theresins cannot be absorbed from the intestine, they are excreted,carrying the bile acids with them. The use of such resins, however, atbest only lowers serum cholesterol levels by about 20%. Moreover, theiruse is associated with gastrointestinal side-effects, includingconstipation and certain vitamin deficiencies. Moreover, since theresins bind to drugs, other oral medications must be taken at least onehour before or four to six hours subsequent to ingestion of the resin,complicating heart patients' drug regimens.

The statins are inhibitors of cholesterol synthesis. Sometimes, thestatins are used in combination therapy with bile-acid-binding resins.Lovastatin (MEVACOR, Merck & Co., Inc.), a natural product derived froma strain of Aspergillus; pravastatin (PRAVACHOL, Bristol-Myers SquibbCo.); and atorvastatin (LIPITOR, Warner Lambert) block cholesterolsynthesis by inhibiting HMGCoA reductase, the key enzyme involved in thecholesterol biosynthetic pathway. Lovastatin significantly reduces serumcholesterol and LDL-serum levels. However, serum HDL levels are onlyslightly increased following lovastatin administration. The mechanism ofthe LDL-lowering effect may involve both reduction of VLDL concentrationand induction of cellular expression of LDL-receptor, leading to reducedproduction and/or increased catabolism of LDL. Side effects, includingliver and kidney dysfunction are associated with the use of these drugs.

Nicotinic acid, also known as niacin, is a water-soluble vitaminB-complex used as a dietary supplement and antihyperlipidemic agent.Niacin diminishes the production of VLDL and is effective at loweringLDL. It is used in combination with bile-acid-binding resins. Niacin canincrease HDL when administered at therapeutically effective doses;however, its usefulness is limited by serious side effects.

Fibrates are a class of lipid-lowering drugs used to treat various formsof hyperlipidemia, elevated serum triglycerides, which may also beassociated with hypercholesterolemia. Fibrates appear to reduce the VLDLfraction and modestly increase HDL; however, the effects of these drugson serum cholesterol is variable. In the United States, fibrates havebeen approved for use as antilipidemic drugs, but have not receivedapproval as hypercholesterolemia agents. For example, clofibrate(ATROMID-S, Wyeth-Ayerst Laboratories) is an antilipidemic agent thatacts to lower serum triglycerides by reducing the VLDL fraction.Although ATROMID-S may reduce serum cholesterol levels in certainpatient subpopulations, the biochemical response to the drug isvariable, and is not always possible to predict which patients willobtain favorable results. ATROMID-S has not been shown to be effectivefor prevention of coronary heart disease. The chemically andpharmacologically related drug, gemfibrozil (LOPID, Parke-Davis), is alipid regulating agent which moderately decreases serum triglyceridesand VLDL cholesterol. LOPED also increases HDL cholesterol, particularlythe HDL2 and HDL3 subfractions, as well as both the AI/AII-HDLfractions. However, the lipid response to LOPID is heterogeneous,especially among different patient populations. Moreover, whileprevention of coronary heart disease was observed in male patientsbetween the ages of 40 and 55 without history or symptoms of existingcoronary heart disease, it is not clear to what extent these findingscan be extrapolated to other patient populations (e.g., women, older andyounger males). Indeed, no efficacy was observed in patients withestablished coronary heart disease. Serious side-effects are associatedwith the use of fibrates, including toxicity; malignancy, particularlymalignancy of gastrointestinal cancer; gallbladder disease; and anincreased incidence in non-coronary mortality. These drugs are notindicated for the treatment of patients with high LDL or low HDL astheir only lipid abnormality.

Oral estrogen replacement therapy may be considered for moderatehypercholesterolemia in post-menopausal women. However, increases in HDLmay be accompanied with an increase in triglycerides. Estrogen treatmentis, of course, limited to a specific patient population, postmenopausalwomen, and is associated with serious side effects, including inductionof malignant neoplasms; gall bladder disease; thromboembolic disease;hepatic adenoma; elevated blood pressure; glucose intolerance; andhypercalcemia.

Long chain carboxylic acids, particularly long chain α,ω-dicarboxylicacids with distinctive substitution patterns, and their simplederivatives and salts, have been disclosed for treating atherosclerosis,obesity, and diabetes (See, e.g., Bisgaier et al., 1998, J. Lipid Res.39:17-30, and references cited therein; International Patent PublicationWO 98/30530; U.S. Pat. No. 4,689,344; International Patent PublicationWO 99/00116; and U.S. Pat. No. 5,756,344). However, some of thesecompounds, for example the α,ω-dicarboxylic acids substituted at theirα,α′-carbons (U.S. Pat. No. 3,773,946), while having serum triglycerideand serum cholesterol-lowering activities, have no value for treatmentof obesity and hypercholesterolemia (U.S. Pat. No. 4,689,344).

U.S. Pat. No. 4,689,344 disclosesβ,β,β′,β′-tetrasubstituted-α,ω-alkanedioic acids that are optionallysubstituted at their α,α,α′,α′-positions, and alleges that they areuseful for treating obesity, hyperlipidemia, and diabetes. According tothis reference, both triglycerides and cholesterol are loweredsignificantly by compounds such as3,3,14,14-tetramethylhexadecane-1,16-dioic acid. U.S. Pat. No. 4,689,344further discloses that the β,β,β′,β′-tetramethyl-alkanediols of U.S.Pat. No. 3,930,024 also are not useful for treating hypercholesterolemiaor obesity.

Other compounds are disclosed in U.S. Pat. No. 4,711,896. In U.S. Pat.No. 5,756,544, α,ω-dicarboxylic acid-terminated dialkane ethers aredisclosed to have activity in lowering certain plasma lipids, includingLp(a), triglycerides, VLDL-cholesterol, and LDL-cholesterol, in animals,and elevating others, such as HDL-cholesterol. The compounds are alsostated to increase insulin sensitivity. In U.S. Pat. No. 4,613,593,phosphates of dolichol, a polyprenol isolated from swine liver, arestated to be useful in regenerating liver tissue, and in treatinghyperuricuria, hyperlipemia, diabetes, and hepatic diseases in general.

U.S. Pat. No. 4,287,200 discloses azolidinedione derivatives withanti-diabetic, hypolipidemic, and anti-hypertensive properties. However,the administration of these compounds to patients can produce sideeffects such as bone marrow depression, and both liver and cardiaccytotoxicity. Further, the compounds disclosed by U.S. Pat. No.4,287,200 stimulate weight gain in obese patients.

It is clear that none of the commercially available cholesterolmanagement drugs has a general utility in regulating lipid, lipoprotein,insulin and glucose levels in the blood. Thus, compounds that have oneor more of these utilities are clearly needed. Further, there is a clearneed to develop safer drugs that are efficacious at lowering serumcholesterol, increasing HDL serum levels, preventing coronary heartdisease, and/or treating existing disease such as atherosclerosis,obesity, diabetes, and other diseases that are affected by lipidmetabolism and/or lipid levels. There is also a clear need to developdrugs that may be used with other lipid-altering treatment regimens in asynergistic manner. There is still a further need to provide usefultherapeutic agents whose solubility and Hydrophile/Lipophile Balance(HLB) can be readily varied.

Citation or identification of any reference in Section 2 of thisapplication is not an admission that such reference is available asprior art to the present invention.

3. SUMMARY OF THE INVENTION

The invention encompasses hydroxyl compounds useful in treating variousdisorders.

The invention further encompasses pharmaceutical compositions comprisingone or more compounds of the invention and a pharmaceutically acceptablevehicle, excipient, or diluent. A pharmaceutically acceptable vehiclecan comprise a carrier, excipient, diluent, or a mixture thereof.

The invention encompasses a method for treating or preventing aging,Alzheimer's Disease, cancer, cardiovascular disease, diabeticnephropathy, diabetic retinopathy, a disorder of glucose metabolism,dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancingreverse lipid transport, hypertension, impotence, inflammation, insulinresistance, lipid elimination in bile, modulating C reactive protein,obesity, oxysterol elimination in bile, pancreatitis, Parkinson'sdisease, a peroxisome proliferator activated receptor-associateddisorder, phospholipid elimination in bile, renal disease, septicemia,metabolic syndrome disorders (e.g., Syndrome X), and a thromboticdisorder, comprising administering to a patient in need of suchtreatment or prevention a therapeutically effective amount of a compoundof the invention or a pharmaceutical composition comprising a compoundof the invention and a pharmaceutically acceptable vehicle, excipient,or diluent.

The invention also encompasses a method for inhibiting hepatic fattyacid and sterol synthesis comprising administering to a patient in needthereof a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition comprising a compound of theinvention and a pharmaceutically acceptable vehicle, excipient, ordiluent.

The invention also encompasses a method of treating or preventing adisease or disorder that is capable of being treated or prevented byincreasing HDL levels, which comprises administering to a patient inneed of such treatment or prevention a therapeutically effective amountof a compound of the invention and a pharmaceutically acceptablevehicle, excipient, or diluent.

The invention also encompasses a method of treating or preventing adisease or disorder that is capable of being treated or prevented bylowering LDL levels, which comprises administering to such patient inneed of such treatment or prevention a therapeutically effective amountof a compound of the invention and a pharmaceutically acceptablevehicle, excipient, or diluent.

The compounds of the invention favorably alter lipid metabolism inanimal models of dyslipidemia at least in part by enhancing oxidation offatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis andtherefore the invention also encompasses methods of treatment orprevention of metabolic syndrome disorders.

The invention further encompasses a method for reducing the fat contentof meat in livestock comprising administering to livestock in need ofsuch fat-content reduction a therapeutically effective amount of acompound of the invention or a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable vehicle,excipient, or diluent.

The invention encompasses a method for reducing the cholesterol contentof a fowl egg comprising administering to a fowl species atherapeutically effective amount of a compound of the invention or apharmaceutical composition comprising a compound of the invention and apharmaceutically acceptable vehicle, excipient, or diluent.

The present invention may be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments of the invention.

4. DEFINITIONS AND ABBREVIATIONS

Apo(a): apolipoprotein(a)

Apo A-I: apolipoprotein A-I

Apo B: apolipoprotein B

Apo E: apolipoprotein E

FH: Familial hypercholesterolemia

FCH: Familial combined hyperlipidemia

GDM: Gestational diabetes mellitus

HDL: High density lipoprotein

IDL: Intermediate density lipoprotein

IDDM: Insulin dependent diabetes mellitus

LDH: Lactate dehdyrogenase

LDL: Low density lipoprotein

Lp(a): Lipoprotein (a)

MODY: Maturity onset diabetes of the young

NIDDM: Non-insulin dependent diabetes mellitus

PPAR: Peroxisome proliferator activated receptor

RXR: Retinoid X receptor

VLDL: Very low density lipoprotein

As used herein, the phrase “compounds of the invention” means compoundsdisclosed herein. Particular compounds of the invention are compounds offormulas I, II, III, IV, and V, and pharmaceutically acceptable salts,hydrates, enantiomers, diastereomer, racemates or mixtures ofstereoisomers thereof. The compounds of the invention are identifiedherein by their chemical structure and/or chemical name. Where acompound is referred to by both a chemical structure and a chemicalname, and the chemical structure and chemical name conflict, thechemical structure is to be accorded more weight.

The compounds of the invention can contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to the invention, the chemical structuresdepicted herein, and therefore the compounds of the invention, encompassall of the corresponding compounds' enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric andstereoisomeric mixtures.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

A compound of the invention is considered optically active orenantiomerically pure (i.e., substantially the R-form or substantiallythe S-form) with respect to a chiral center when the compound is about90% ee (enantiomeric excess) or greater, preferably, equal to or greaterthan 95% ee with respect to a particular chiral center. A compound ofthe invention is considered to be in enantiomerically-enriched form whenthe compound has an enantiomeric excess of greater than about 1% ee,preferably greater than about 5% ee, more preferably, greater than about10% ee with respect to a particular chiral center. A compound of theinvention is considered diastereomerically pure with respect to multiplechiral centers when the compound is about 90% de (diastereomeric excess)or greater, preferably, equal to or greater than 95% de with respect toa particular chiral center. A compound of the invention is considered tobe in diastereomerically-enriched form when the compound has andiastereomeric excess of greater than about 1% de, preferably greaterthan about 5% de, more preferably, greater than about 10% de withrespect to a particular chiral center. As used herein, a racemic mixturemeans about 50% of one enantiomer and about 50% of is correspondingenantiomer relative to all chiral centers in the molecule. Thus, theinvention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of compounds of Formulas I through V.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

When administered to a patient, e.g., to an animal for veterinary use orfor improvement of livestock, or to a human for clinical use, thecompounds of the invention are administered in isolated form or as theisolated form in a pharmaceutical composition. As used herein,“isolated” means that the compounds of the invention are separated fromother components of either (a) a natural source, such as a plant orcell, preferably bacterial culture, or (b) a synthetic organic chemicalreaction mixture. Preferably, via conventional techniques, the compoundsof the invention are purified. As used herein, “purified” means thatwhen isolated, the isolate contains at least 95%, preferably at least98%, of a single hydroxy compound of the invention by weight of theisolate.

The phrase “pharmaceutically acceptable salt(s),” as used hereinincludes, but is not limited to, salts of acidic or basic groups thatmay be present in the compounds of the invention. Compounds that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfuric, citric, maleic, acetic, oxalic, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds of theinvention that include an amino moiety also can form pharmaceuticallyacceptable salts with various amino acids, in addition to the acidsmentioned above. Compounds of the invention that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts and, particularly, calcium, magnesium, sodiumlithium, zinc, potassium, and iron salts.

As used herein, the term “hydrate” means a compound of the invention ora salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces. The term hydrate includes solvates, which are stoichiometric ornon-stoichiometric amounts of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

As used herein, the term “altering lipid metabolism” indicates anobservable (measurable) change in at least one aspect of lipidmetabolism, including but not limited to total blood lipid content,blood HDL cholesterol, blood LDL cholesterol, blood VLDL cholesterol,blood triglyceride, blood Lp(a), blood apo A-I, blood apo E and bloodnon-esterified fatty acids.

As used herein, the term “altering glucose metabolism” indicates anobservable (measurable) change in at least one aspect of glucosemetabolism, including but not limited to total blood glucose content,blood insulin, the blood insulin to blood glucose ratio, insulinsensitivity, and oxygen consumption.

As used herein, the term “alkyl group” means a saturated, monovalentunbranched or branched hydrocarbon chain. Examples of alkyl groupsinclude, but are not limited to, (C₁-C₆)alkyl groups, such as methyl,ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2 methyl 2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2 methyl-3-butyl, 2,2 dimethyl1-propyl, 2-methyl-1-pentyl, 3 methyl-1-pentyl, 4 methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl 2 pentyl, 2,2 dimethyl 1butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl,pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, suchas heptyl, and octyl. An alkyl group can be unsubstituted or substitutedwith one or two suitable substituents.

As used herein, the term an “alkenyl group” means a monovalentunbranched or branched hydrocarbon chain having one or more double bondstherein. The double bond of an alkenyl group can be unconjugated orconjugated to another unsaturated group. Suitable alkenyl groupsinclude, but are not limited to (C₂-C₆)alkenyl groups, such as vinyl,allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl,2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. Analkenyl group can be unsubstituted or substituted with one or twosuitable substituents.

As used herein, the term an “alkynyl group” means monovalent unbranchedor branched hydrocarbon chain having one or more triple bonds therein.The triple bond of an alkynyl group can be unconjugated or conjugated toanother unsaturated group. Suitable alkynyl groups include, but are notlimited to, (C₂-C₆)alkynyl groups, such as ethynyl, propynyl, butynyl,pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl,4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. An alkynyl group can beunsubstituted or substituted with one or two suitable substituents.

As used herein, the term an “aryl group” means a monocyclic orpolycyclic-aromatic radical comprising carbon and hydrogen atoms.Examples of suitable aryl groups include, but are not limited to,phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl,as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, the arylgroup is a monocyclic ring, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)aryl”.

As used herein, the term an “heteroaryl group” means a monocyclic- orpolycyclic aromatic ring comprising carbon atoms, hydrogen atoms, andone or more heteroatoms, preferably 1 to 3 heteroatoms, independentlyselected from nitrogen, oxygen, and sulfur. Illustrative examples ofheteroaryl groups include, but are not limited to, pyridinyl,pyridazinyl, pyrimidinyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl,imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl,tetrazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, furyl, phenyl,isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, aheteroaryl group is a monocyclic ring, wherein the ring comprises 2 to 5carbon atoms and 1 to 3 heteroatoms, referred to herein as“(C₂-C₅)heteroaryl”.

As used herein, the term “cycloalkyl group” means a monocyclic orpolycyclic saturated ring comprising carbon and hydrogen atoms andhaving no carbon-carbon multiple bonds. Examples of cycloalkyl groupsinclude, but are not limited to, (C₃-C₇)cycloalkyl groups, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, andsaturated cyclic and bicyclic terpenes. A cycloalkyl group can beunsubstituted or substituted by one or two suitable substituents.Preferably, the cycloalkyl group is a monocyclic ring or bicyclic ring.

As used herein, the term “heterocycloalkyl group” means a monocyclic orpolycyclic ring comprising carbon and hydrogen atoms and at least oneheteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen,oxygen, and sulfur, and having no unsaturation. Examples ofheterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl,piperidino, piperazinyl, piperazino, morpholinyl, morpholino,thiomorpholinyl, thiomorpholino, and pyranyl. A heterocycloalkyl groupcan be unsubstituted or substituted with one or two suitablesubstituents. Preferably, the heterocycloalkyl group is a monocyclic orbicyclic ring, more preferably, a monocyclic ring, wherein the ringcomprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referredto herein as (C₁-C₆)heterocycloalkyl.

As used herein, the terms “heterocyclic radical” or “heterocyclic ring”mean a heterocycloalkyl group or a heteroaryl group.

As used herein, the term “alkoxy group” means an —O-alkyl group, whereinalkyl is as defined above. An alkoxy group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, the alkylchain of an alkyloxy group is from 1 to 6 carbon atoms in length,referred to herein as “(C₁-C₆)alkoxy”.

As used herein, the term “aryloxy group” means an —O-aryl group, whereinaryl is as defined above. An aryloxy group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, the arylring of an aryloxy group is a monocyclic ring, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryloxy”.

As used herein, the term “benzyl” means —CH₂-phenyl.

As used herein, the term “phenyl” means —C₆H₅. A phenyl group can beunsubstituted or substituted with one or two suitable substituents,wherein the substituent replaces an H of the phenyl group. As usedherein, “Ph,” represents a phenyl group or a substituted phenyl group.

As used herein, the term “hydrocarbyl” group means a monovalent groupselected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, and (C₂-C₈)alkynyl,optionally substituted with one or two suitable substituents.Preferably, the hydrocarbon chain of a hydrocarbyl group is from 1 to 6carbon atoms in length, referred to herein as “(C₁-C₆)hydrocarbyl”.

As used herein, a “carbonyl” group is a divalent group of the formulaC(O).

As used herein, the term “alkoxycarbonyl” group means a monovalent groupof the formula —C(O)-alkoxy. Preferably, the hydrocarbon chain of analkoxycarbonyl group is from 1 to 8 carbon atoms in length, referred toherein as a “lower alkoxycarbonyl” group.

As used herein, a “carbamoyl” group means the radical —C(O)N(R′)₂,wherein R′ is chosen from the group consisting of hydrogen, alkyl, andaryl.

As used herein, “halogen” means fluorine, chlorine, bromine, or iodine.Accordingly, the meaning of the terms “halo” and “Hal” encompass fluoro,chloro, bromo, and iodo.

As used herein, a “suitable substituent” means a group that does notnullify the synthetic or pharmaceutical utility of the compounds of theinvention or the intermediates useful for preparing them. Examples ofsuitable substituents include, but are not limited to: (C₁-C₈)alkyl;(C₁-C₈)alkenyl; (C₁-C₈)alkynyl; (C₆)aryl; (C₂-C₅)heteroaryl;(C₃-C₇)cycloalkyl; (C₁-C₈)alkoxy; (C₆)aryloxy; —CN; —OH; oxo; halo,—CO₂H; —NH₂; —NH((C₁-C₈)alkyl); —N((C₁-C₈)alkyl)₂; —NH((C₆)aryl);—N((C₆)aryl)₂; —CHO; —CO((C₁-C₈)alkyl); —CO((C₆)aryl);—CO₂((C₁-C₈)alkyl); and —CO₂((C₆)aryl). One of skill in the art canreadily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the compound of the invention.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

5. DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention are useful in medical applications fortreating or preventing a variety of diseases and disorders such as, butnot limited to, cardiovascular disease, stroke, and peripheral vasculardisease; dyslipidemia; dyslipoproteinemia; a disorder of glucosemetabolism; Alzheimer's Disease; Parkinson's Disease, diabeticnephropathy, diabetic retinopathy, insulin resistance, Syndrome X; aperoxisome proliferator activated receptor-associated disorder;septicemia; a thrombotic disorder; obesity; pancreatitis; hypertension;renal disease; cancer; inflammation; inflammatory muscle diseases, suchas polymylagia rheumatica, polymyositis, and fibrositis; impotence;gastrointestinal disease; irritable bowel syndrome; inflammatory boweldisease; inflammatory disorders, such as asthma, vasculitis, ulcerativecolitis, Crohn's disease, Kawasaki disease, Wegener's granulomatosis,(RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), andautoimmune chronic hepatitis; arthritis, such as rheumatoid arthritis,juvenile rheumatoid arthritis, and osteoarthritis; osteoporosis, softtissue rheumatism, such as tendonitis; bursitis; autoimmune disease,such as systemic lupus and erythematosus; scleroderma; ankylosingspondylitis; gout; pseudogout; non-insulin dependent diabetes mellitus;polycystic ovarian disease; hyperlipidemias, such as familialhypercholesterolemia (FH), familial combined hyperlipidemia (FCH);lipoprotein lipase deficiencies, such as hypertriglyceridemia,hypoalphalipoproteinemia, and hypercholesterolemia; lipoproteinabnormalities associated with diabetes; lipoprotein abnormalitiesassociated with obesity; and lipoprotein abnormalities associated withAlzheimer's Disease. The compounds and compositions of the invention areuseful for treatment or prevention of high levels of bloodtriglycerides, high levels of low density lipoprotein cholesterol, highlevels of apolipoprotein B, high levels of lipoprotein Lp(a)cholesterol, high levels of very low density lipoprotein cholesterol,high levels of fibrinogen, high levels of insulin, high levels ofglucose, and low levels of high density lipoprotein cholesterol. Thecompounds and compositions of the invention also have utility fortreatment of NIDDM without increasing weight gain. The compounds of theinvention may also be used to reduce the fat content of meat inlivestock and reduce the cholesterol content of eggs.

The invention provides novel compounds particularly useful for treatingor preventing a variety of diseases and conditions, which include, butare not limited to aging, Alzheimer's Disease, cancer, cardiovasculardisease, diabetic nephropathy, diabetic retinopathy, a disorder ofglucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bileproduction, hypertension, impotence, inflammation, insulin resistance,lipid elimination in bile, modulating C reactive protein, obesity,oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson'sdisease, a peroxisome proliferator activated receptor-associateddisorder, phospholipid elimination in bile, renal disease, septicemia,metabolic syndrome disorders (e.g., Syndrome X), and a thromboticdisorder.

The invention encompasses compounds of formula I:

or a pharmaceutically acceptable salt, hydrate, solvate or a mixturethereof, wherein:

-   (a) each occurrence of m is independently an integer ranging from 0    to 5;-   (b) each occurrence of n is independently an integer ranging from 3    to 7;-   (c) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4;-   (d) each occurrence of R¹ and R² is independently (C₁-C₆)alkyl,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, benzyl, or R¹ and R² and the    carbon to which they are both attached are taken together to form a    (C₃-C₇)cycloakyl group;-   (e) each occurrence of R¹¹ and R¹² and the carbon to which they are    both attached are taken together to form a (C₃-C₇)cycloakyl group;-   (f) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl, OH,    COOH, COOR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups; and    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.

In an exemplary compound of formula I, each occurrence of Y isindependently OH, COOR³, or COOH.

Other compounds of formula I are those wherein m is 0.

Other compounds of formula I are those wherein m is 1.

Other compounds of formula I are those wherein n is 4.

Other compounds of formula I are those wherein n is 5.

Other compounds of formula I are those wherein z is 0.

Other compounds of formula I are those wherein z is 1.

Other compounds of formula I are those wherein Y¹ and Y² are eachindependently (C₁-C₆)alkyl.

Other compounds of formula I are those wherein Y¹ and Y² are eachmethyl.

Other compounds of formula I are those wherein each occurrence R¹ and R²and the carbon to which they are both attached are taken together toform a (C₃-C₇)cycloakyl group.

In another embodiment, the invention encompasses compounds of theformula II:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   (a) each occurrence of R¹ and R² is independently (C₁-C₆)alkyl,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, benzyl, or R¹ and R² and the    carbon to which they are both attached are taken together to form a    (C₃-C₇)cycloakyl group;-   (b) each occurrence of R¹¹ and R¹² and the carbon to which they are    both attached are taken together to form a (C₃-C₇)cycloakyl group;-   (c) each occurrence of n is independently an integer ranging from 1    to 7;-   (d) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4;-   (e) each occurrence of m is independently an integer ranging from 0    to 4;-   (f) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,    CH₂OH, C(O)OH, OC(O)R³, C(O)OR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups;    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and

-   (g) b is 0 or 1 or optionally the presence of one or more additional    carbon-carbon bonds that when present complete one or more    carbon-carbon double bonds.

Exemplary compounds of formula II are those in which each occurrence ofR¹ and R² and the carbon to which they are both attached are takentogether to form a (C₃-C₇)cycloakyl group.

In another embodiment, the invention encompasses compounds of formulaIII:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturesthereof, wherein:

-   (a) each occurrence of R¹ and R² is independently (C₁-C₆)alkyl,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, benzyl, or R¹ and R² and the    carbon to which they are both attached are taken together to form a    (C₃-C₇)cycloakyl group;-   (b) each occurrence of R¹¹ and R¹² and the carbon to which they are    both attached are taken together to form a (C₃-C₇)cycloakyl group;-   (c) each occurrence of n is independently an integer ranging from 1    to 7;-   (d) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4;-   (e) each occurrence of m is independently an integer ranging from 0    to 4;-   (f) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,    CH₂OH, C(O)OH, OC(O)R³, C(O)OR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups;    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and

-   (f) each occurrence of b is independently 0 or 1 or optionally the    presence of one or more additional carbon-carbon bonds that when    present complete one or more carbon-carbon double bonds.

In another embodiment, the invention encompasses compounds of formulaIV:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   (a) each occurrence of R¹ and R² is independently (C₁-C₆)alkyl,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, benzyl, or R¹ and R² and the    carbon to which they are both attached are taken together to form a    (C₃-C₇)cycloakyl group;-   (b) each occurrence of R¹¹ and R¹² and the carbon to which they are    both attached are taken together to form a (C₃-C₇)cycloakyl group;-   (c) each occurrence of n is independently an integer ranging from 1    to 7;-   (d) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4;-   (e) each occurrence of m is independently an integer ranging from 0    to 4;-   (f) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,    CH₂OH, C(O)OH, OC(O)R³, C(O)OR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups;    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; and

-   (g) b is 0 or 1 or optionally the presence of one or more additional    carbon-carbon bonds that when present complete one or more    carbon-carbon double bonds.

In another embodiment, the invention encompasses compounds of formula V:

or a pharmaceutically acceptable salt, hydrate, solvate, or mixturethereof, wherein

-   (a) each occurrence of R¹ and R² is independently (C₁-C₆)alkyl,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, benzyl, or R¹ and R² and the    carbon to which they are both attached are taken together to form a    (C₃-C₇)cycloakyl group;-   (b) each occurrence of R¹¹ and R¹² and the carbon to which they are    both attached are taken together to form a (C₃-C₇)cycloakyl group;-   (c) each occurrence of n is independently an integer ranging from 1    to 7;-   (d) X is (CH₂)_(z) or Ph, wherein z is an integer from 0 to 4;-   (e) each occurrence of m is independently an integer ranging from 0    to 4; and-   (f) each occurrence of Y¹ and Y² is independently (C₁-C₆)alkyl,    CH₂OH, C(O)OH, OC(O)R³, C(O)OR³, SO₃H,

wherein:

-   -   (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,        or benzyl and is unsubstituted or substituted with one or more        halo, OH, (C₁-C₆)alkoxy, or phenyl groups,    -   (ii) each occurrence of R⁴ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and is unsubstituted or        substituted with one or two halo, OH, C₁-C₆ alkoxy, or phenyl        groups; and    -   (iii) each occurrence of R⁵ is independently H, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.

The present invention further encompasses pharmaceutical compositionscomprising one or more compounds of the invention. Particularpharmaceutical compositions further comprise pharmaceutically acceptablevehicle, which can comprise a carrier, excipient, diluent, or a mixturethereof.

The present invention encompasses a method for treating or preventingaging, Alzheimer's Disease, cancer, cardiovascular disease, diabeticnephropathy, diabetic retinopathy, a disorder of glucose metabolism,dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancingreverse lipid transport, hypertension, impotence, inflammation, insulinresistance, lipid elimination in bile, modulating C reactive protein,obesity, oxysterol elimination in bile, pancreatitis, Parkinson'sdisease, a peroxisome proliferator activated receptor-associateddisorder, phospholipid elimination in bile, renal disease, septicemia,metabolic syndrome disorders (e.g., Syndrome X), and a thromboticdisorder, comprising administering to a patient in need of suchtreatment or prevention a therapeutically effective amount of a compoundof the invention.

The present invention further encompasses a method of treating orpreventing a disease or disorder that is capable of being treated orprevented by increasing HDL levels, which comprises administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of a compound.

The present invention further encompasses a method of treating orpreventing a disease or disorder that is capable of being treated orprevented by decreasing LDL levels, which comprises administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of a compound.

The present invention further encompasses a method for reducing the fatcontent of meat in livestock comprising administering to livestock inneed of such fat-content reduction a therapeutically effective amount ofa compound of the invention or a pharmaceutical composition.

The present invention encompasses a method for reducing the cholesterolcontent of a fowl egg comprising administering to a fowl species atherapeutically effective amount of a compound of the invention.

The compounds of the invention are particularly useful when incorporatedin a pharmaceutical composition comprising a carrier, excipient,diluent, or a mixture thereof. However, a compound of the invention neednot be administered with excipients or diluents and can be delivered ina gel cap or drug delivery device.

In certain embodiments of the invention, a compound of the invention isadministered in combination with another therapeutic agent. The othertherapeutic agent provides additive or synergistic value relative to theadministration of a compound of the invention alone. Examples of othertherapeutic agents include, but are not limited to, a lovastatin; athiazolidinedione or fibrate; a bile-acid-binding-resin; a niacin; ananti-obesity drug; a hormone; a tyrophostine; a sulfonylurea-based drug;a biguanide; an α-glucosidase inhibitor; an apolipoprotein A-I agonist;apolipoprotein E; a cardiovascular drug; an HDL-raising drug; an HDLenhancer; or a regulator of the apolipoprotein A-I, apolipoprotein A-IVand/or apolipoprotein genes.

Illustrative examples of compounds of the invention include those shownbelow, and pharmaceutically acceptable salts, hydrates, enantiomers,diastereomers, and geometric isomers thereof:

5.1 Synthesis of the Compounds of the Invention

The compounds of the invention can be obtained via the syntheticmethodology illustrated in Scheme 1. Starting materials useful forpreparing the compounds of the invention and intermediates thereof, arecommercially available or can be prepared form commercially availablematerials using known synthetic methods and reagents.

Scheme 1 illustrates the synthesis of cycloalkyl-hydroxyl compounds ofthe formula 2 and 4 wherein n is an integer in the range from 2-12 and mis an integer in the range from 1-4.

Compounds 1 and 3 are prepared as described in Dasseux et al. U.S.patent application Ser. No. 09/976,938, filed Oct. 11, 2001, which isincorporated herein by reference in its entirety. Compounds 2 and 4 areprepared from ketones of type 1 and 3, respectively by well-knownreductive methods (see, Larock, R. C. Comprehensive OrganicTransformations; A Guide To Functional Group Preparations, 1989, pp527-548, for a discussion of various methods for conversion of ketonesto alcohols see, March, J. Advanced Organic Chemistry; Reactions,Mechanisms, and structure, 4th ed., 1992, pp 910-918). For example,metalhydride reductions (e.g. lithium aluminum hydride, see Takazawa,O.; Kogami, K.; Hayashi, K., Chem. Lett., 1983, 63-64, lithiumtri-tert-butoxyaluminohydride, see Mander, L. N.; Palmer, L. T., Aust.J. Chem., 1979, 32, 823-832 or sodium borohydride (Kishimoto, S.; etal., Chem. Pharm. Bull., 1974, 22, 2231-2241, Mohr, P., TetrahedronLett., 1995, 36, 7221-7224, Metzger, J. O.; Biermann, U., Liebigs Ann.Chem., 1993, 6, 645-650, Kennedy, J.; et al., J. Chem. Soc., 1961,4945-4948)), catalytic hydrogenation catalyzed by transition metals(e.g. Raney nickel, see Zakharkin, L. I.; Guseva, V. V.; Churilova, I.M.; J. Org. Chem. USSR, 1983, 19, 1632-1634, platinum, see Ficini, J.;et al., J. Am. Chem Soc., 1974, 96, 1213-1214 or ruthenium, see Bowden,R. D.; Cooper, R. D. G.; Harris, C. J.; Moss, G. P.; Weedon, B. C. L.;Jackman, L. M., J. Chem. Soc. Perkin Trans. 1, 1983, 7, 1465-1474),metal or dissolving metal reductions (e.g. lithium, see Maiti, S. B.;Kundu, A. P.; Chatterjee, A.; Raychaudhuri, S. R., Indian J. Chem. Sect.B, 1986, 15-21) and reductions catalyzed by enzymes (e.g. Baker's yeast,see Utaka, M.; Watabu, H.; Takeda, A., J. Org. Chem., 1987, 52,4363-4368).

In a typical example, compound of formula 2 is prepared starting fromthe corresponding ketone 1 by treatment with lithium aluminum hydride(Takazawa, O.; Kogami, K.; Hayashi, K., Chem. Lett., 1983, 63-64),lithium tri-tert-butoxyaluminohydride (Mander, L. N.; Palmer, L. T.,Aust. J. Chem., 1979, 32, 823-832), or preferably sodium borohydride(Kishimoto, S.; et al., Chem. Pharm. Bull., 1974, 22, 2231-2241, Mohr,P., Tetrahedron Lett., 1995, 36, 7221-7224, Metzger, J. O.; Biermann,U., Liebigs Ann. Chem., 1993, 6, 645-650, Kennedy, J.; et al., J. Chem.Soc., 1961, 4945-4948), preferably though not limited to temperaturesbetween 0° C. and room temperature. Preferably though not limited, thereaction is run in a protic solvent where ethanol or isopropanol are themost preferred ones. Further, the reaction can be performed in thepresence of a basic aqueous solution; preferably a solution of sodiumhydroxide in water or a Lewis acid catalyst, preferably CeCl₃ (Gemal, A.L.; Luche, J.-L., J. Am Cem. Soc., 1981, 103, 5454, Cooley, G.; Kirk, D.N., J. Chem. Soc. Perkin Trans. I, 1984, 6, 1205-1212). Each of thereferences disclosed herein are incorporated by reference in theirentirety.

5.2 Therapeutic Uses of Compounds or Compositions of the Invention

In accordance with the invention, a compound of the invention or acomposition of the invention, comprising a compound of the invention anda pharmaceutically acceptable vehicle, is administered to a patient,preferably a human, with or at risk of aging, Alzheimer's Disease,cancer, cardiovascular disease, diabetic nephropathy, diabeticretinopathy, a disorder of glucose metabolism, dyslipidemia,dyslipoproteinemia, enhancing bile production, enhancing reverse lipidtransport, hypertension, impotence, inflammation, insulin resistance,lipid elimination in bile, modulating C reactive protein, obesity,oxysterol elimination in bile, pancreatitis, Parkinson's disease, aperoxisome proliferator activated receptor-associated disorder,phospholipid elimination in bile, renal disease, septicemia, metabolicsyndrome disorders (e.g., Syndrome X), a thrombotic disorder,gastrointestinal disease, irritable bowel syndrome (IBS), inflammatorybowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis(e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g.,systemic lupus erythematosus), scleroderma, ankylosing spondylitis, goutand pseudogout, muscle pain: polymyositis/polymyalgiarheumatica/fibrositis; infection and arthritis, juvenile rheumatoidarthritis, tendonitis, bursitis and other soft tissue rheumatism. In oneembodiment, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to inhibiting theprogression of a disease or disorder, either physically, e.g.,stabilization of a discernible symptom, physiologically, e.g.,stabilization of a physical parameter, or both.

In certain embodiments, the compounds of the invention or thecompositions of the invention are administered to a patient, preferablya human, as a preventative measure against such diseases. As usedherein, “prevention” or “preventing” refers to a reduction of the riskof acquiring a given disease or disorder. In a preferred mode of theembodiment, the compositions of the present invention are administeredas a preventative measure to a patient, preferably a human having agenetic predisposition to a aging, Alzheimer's Disease, cancer,cardiovascular disease, diabetic nephropathy, diabetic retinopathy, adisorder of glucose metabolism, dyslipidemia, dyslipoproteinemia,enhancing bile production, enhancing reverse lipid transport,hypertension, impotence, inflammation, insulin resistance, lipidelimination in bile, modulating C reactive protein, obesity, oxysterolelimination in bile, pancreatitis, Parkinson's disease, a peroxisomeproliferator activated receptor-associated disorder, phospholipidelimination in bile, renal disease, septicemia, metabolic syndromedisorders (e.g., Syndrome X), a thrombotic disorder, inflammatoryprocesses and diseases like gastrointestinal disease, irritable bowelsyndrome (IBS), inflammatory bowel disease (e.g., Crohn's Disease,ulcerative colitis), arthritis (e.g., rheumatoid arthritis,osteoarthritis), autoimmune disease (e.g., systemic lupuserythematosus), scleroderma, ankylosing spondylitis, gout andpseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis;infection and arthritis, juvenile rheumatoid arthritis, tendonitis,bursitis and other soft tissue rheumatism. Examples of such geneticpredispositions include but are not limited to the ε4 allele ofapolipoprotein E, which increases the likelihood of Alzheimer's Disease;a loss of function or null mutation in the lipoprotein lipase genecoding region or promoter (e.g., mutations in the coding regionsresulting in the substitutions D9N and N291S; for a review of geneticmutations in the lipoprotein lipase gene that increase the risk ofcardiovascular diseases, dyslipidemias and dyslipoproteinemias, seeHayden and Ma, 1992, Mol. Cell Biochem. 113:171-176); and familialcombined hyperlipidemia and familial hypercholesterolemia.

In another preferred mode of the embodiment, the compounds of theinvention or compositions of the invention are administered as apreventative measure to a patient having a non-genetic predisposition toa aging, Alzheimer's Disease, cancer, cardiovascular disease, diabeticnephropathy, diabetic retinopathy, a disorder of glucose metabolism,dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancingreverse lipid transport, hypertension, impotence, inflammation, insulinresistance, lipid elimination in bile, modulating C reactive protein,obesity, oxysterol elimination in bile, pancreatitis, Parkinson'sdisease, a peroxisome proliferator activated receptor-associateddisorder, phospholipid elimination in bile, renal disease, septicemia,metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder,inflammatory processes and diseases like gastrointestinal disease,irritable bowel syndrome (IBS), inflammatory bowel disease (e.g.,Crohn's Disease, ulcerative colitis), arthritis (e.g., rheumatoidarthritis, osteoarthritis), autoimmune disease (e.g., systemic lupuserythematosus), scleroderma, ankylosing spondylitis, gout andpseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis;infection and arthritis, juvenile rheumatoid arthritis, tendonitis,bursitis and other soft tissue rheumatism. Examples of such non-geneticpredispositions include but are not limited to cardiac bypass surgeryand percutaneous transluminal coronary angioplasty, which often lead torestenosis, an accelerated form of atherosclerosis; diabetes in women,which often leads to polycystic ovarian disease; and cardiovasculardisease, which often leads to impotence. Accordingly, the compositionsof the invention may be used for the prevention of one disease ordisorder and concurrently treating another (e.g., prevention ofpolycystic ovarian disease while treating diabetes; prevention ofimpotence while treating a cardiovascular disease).

5.2.1 Treatment of Cardiovascular Diseases

The present invention provides methods for the treatment or preventionof a cardiovascular disease, comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle. As used herein, the term “cardiovascular diseases” refers todiseases of the heart and circulatory system. These diseases are oftenassociated with dyslipoproteinemias and/or dyslipidemias. Cardiovasculardiseases which the compositions of the present invention are useful forpreventing or treating include but are not limited to arteriosclerosis;atherosclerosis; stroke; ischemia; endothelium dysfunctions, inparticular those dysfunctions affecting blood vessel elasticity;peripheral vascular disease; coronary heart disease; myocardialinfarcation; cerebral infarction and restenosis.

5.2.2 Treatment of Dyslipidemias

The present invention provides methods for the treatment or preventionof a dyslipidemia comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle.

As used herein, the term “dyslipidemias” refers to disorders that leadto or are manifested by aberrant levels of circulating lipids. To theextent that levels of lipids in the blood are too high, the compositionsof the invention are administered to a patient to restore normal levels.Normal levels of lipids are reported in medical treatises known to thoseof skill in the art. For example, recommended blood levels of LDL, HDL,free triglycerides and others parameters relating to lipid metabolismcan be found at the web site of the American Heart Association and thatof the National Cholesterol Education Program of the National Heart,Lung and Blood Institute(http://www.americanheart.org/cholesterol/about_level.html andhttp://www.nhlbi.nih.gov/health/public/heart/chol/hbc_what.html,respectively). At the present time, the recommended level of HDLcholesterol in the blood is above 35 mg/dL; the recommended level of LDLcholesterol in the blood is below 130 mg/dL; the recommended LDL:HDLcholesterol ratio in the blood is below 5:1, ideally 3.5:1; and therecommended level of free triglycerides in the blood is less than 200mg/dL.

Dyslipidemias which the compositions of the present invention are usefulfor preventing or treating include but are not limited to hyperlipidemiaand low blood levels of high density lipoprotein (HDL) cholesterol. Incertain embodiments, the hyperlipidemia for prevention or treatment bythe compounds of the present invention is familial hypercholesterolemia;familial combined hyperlipidemia; reduced or deficient lipoproteinlipase levels or activity, including reductions or deficienciesresulting from lipoprotein lipase mutations; hypertriglyceridemia;hypercholesterolemia; high blood levels of urea bodies (e.g. β-OHbutyric acid); high blood levels of Lp(a) cholesterol; high blood levelsof low density lipoprotein (LDL) cholesterol; high blood levels of verylow density lipoprotein (VLDL) cholesterol and high blood levels ofnon-esterified fatty acids.

The present invention further provides methods for altering lipidmetabolism in a patient, e.g., reducing LDL in the blood of a patient,reducing free triglycerides in the blood of a patient, increasing theratio of HDL to LDL in the blood of a patient, and inhibiting saponifiedand/or non-saponified fatty acid synthesis, said methods comprisingadministering to the patient a compound or a composition comprising acompound of the invention in an amount effective alter lipid metabolism.

5.2.3 Treatment of Dyslipoproteinemias

The present invention provides methods for the treatment or preventionof a dyslipoproteinemia comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle.

As used herein, the term “dyslipoproteinemias” refers to disorders thatlead to or are manifested by aberrant levels of circulatinglipoproteins. To the extent that levels of lipoproteins in the blood aretoo high, the compositions of the invention are administered to apatient to restore normal levels. Conversely, to the extent that levelsof lipoproteins in the blood are too low, the compositions of theinvention are administered to a patient to restore normal levels. Normallevels of lipoproteins are reported in medical treatises known to thoseof skill in the art.

Dyslipoproteinemias which the compositions of the present invention areuseful for preventing or treating include but are not limited to highblood levels of LDL; high blood levels of apolipoprotein B (apo B); highblood levels of Lp(a); high blood levels of apo(a); high blood levels ofVLDL; low blood levels of HDL; reduced or deficient lipoprotein lipaselevels or activity, including reductions or deficiencies resulting fromlipoprotein lipase mutations; hypoalphalipoproteinemia; lipoproteinabnormalities associated with diabetes; lipoprotein abnormalitiesassociated with obesity; lipoprotein abnormalities associated withAlzheimer's Disease; and familial combined hyperlipidemia.

The present invention further provides methods for reducing apo C-IIlevels in the blood of a patient; reducing apo C-III levels in the bloodof a patient; elevating the levels of HDL associated proteins, includingbut not limited to apo A-I, apo A-II, apo A-N and apo E in the blood ofa patient; elevating the levels of apo E in the blood of a patient, andpromoting clearance of triglycerides from the blood of a patient, saidmethods comprising administering to the patient a compound or acomposition comprising a compound of the invention in an amounteffective to bring about said reduction, elevation or promotion,respectively.

5.2.4 Treatment of Glucose Metabolism Disorders

The present invention provides methods for the treatment or preventionof a glucose metabolism disorder, comprising administering to a patienta therapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle. As used herein, the term “glucose metabolism disorders” refersto disorders that lead to or are manifested by aberrant glucose storageand/or utilization. To the extent that indicia of glucose metabolism(i.e., blood insulin, blood glucose) are too high, the compositions ofthe invention are administered to a patient to restore normal levels.Conversely, to the extent that indicia of glucose metabolism are toolow, the compositions of the invention are administered to a patient torestore normal levels. Normal indicia of glucose metabolism are reportedin medical treatises known to those of skill in the art.

Glucose metabolism disorders which the compositions of the presentinvention are useful for preventing or treating include but are notlimited to impaired glucose tolerance; insulin resistance; insulinresistance related breast, colon or prostate cancer; diabetes, includingbut not limited to non-insulin dependent diabetes mellitus (NIDDM),insulin dependent diabetes mellitus (IDDM), gestational diabetesmellitus (GDM), and maturity onset diabetes of the young (MODY);pancreatitis; hypertension; polycystic ovarian disease; and high levelsof blood insulin and/or glucose.

The present invention further provides methods for altering glucosemetabolism in a patient, for example to increase insulin sensitivityand/or oxygen consumption of a patient, said methods comprisingadministering to the patient a compound or a composition comprising acompound of the invention in an amount effective to alter glucosemetabolism.

5.2.5 Treatment of PPAR-Associated Disorders

The present invention provides methods for the treatment or preventionof a PPAR-associated disorder, comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle. As used herein, “treatment or prevention of PPAR associateddisorders” encompasses treatment or prevention of rheumatoid arthritis;multiple sclerosis; psoriasis; inflammatory bowel diseases; breast;colon or prostate cancer; low levels of blood HDL; low levels of blood,lymph and/or cerebrospinal fluid apo E; low blood, lymph and/orcerebrospinal fluid levels of apo A-I; high levels of blood VLDL; highlevels of blood LDL; high levels of blood triglyceride; high levels ofblood apo B; high levels of blood apo C-III and reduced ratio ofpost-heparin hepatic lipase to lipoprotein lipase activity. HDL may beelevated in lymph and/or cerebral fluid.

5.2.6 Treatment of Renal Diseases

The present invention provides methods for the treatment or preventionof a renal disease, comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle. Renal diseases that can be treated by the compounds of thepresent invention include glomerular diseases (including but not limitedto acute and chronic glomerulonephritis, rapidly progressiveglomerulonephritis, nephrotic syndrome, focal proliferativeglomerulonephritis, glomerular lesions associated with systemic disease,such as systemic lupus erythematosus, Goodpasture's syndrome, multiplemyeloma, diabetes, neoplasia, sickle cell disease, and chronicinflammatory diseases), tubular diseases (including but not limited toacute tubular necrosis and acute renal failure, polycystic renaldiseasemedullary sponge kidney, medullary cystic disease, nephrogenicdiabetes, and renal tubular acidosis), tubulointerstitial diseases(including but not limited to pyelonephritis, drug and toxin inducedtubulointerstitial nephritis, hypercalcemic nephropathy, and hypokalemicnephropathy) acute and rapidly progressive renal failure, chronic renalfailure, nephrolithiasis, or tumors (including but not limited to renalcell carcinoma and nephroblastoma). In a most preferred embodiment,renal diseases that are treated by the compounds of the presentinvention are vascular diseases, including but not limited tohypertension, nephrosclerosis, microangiopathic hemolytic anemia,atheroembolic renal disease, diffuse cortical necrosis, and renalinfarcts.

5.2.7 Treatment of Cancer

The present invention provides methods for the treatment or preventionof cancer, comprising administering to a patient a therapeuticallyeffective amount of a compound or a composition comprising a compound ofthe invention and a pharmaceutically acceptable vehicle. Types of cancerthat can be treated using a Compound of the Invention include, but arenot limited to, those listed in Table 2.

TABLE 2 Solid tumors, including but not limited to fibrosarcomamyxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordomaangiosarcoma endotheliosarcoma lymphangiosarcomalymphangioendotheliosarcoma synovioma mesothelioma Ewing's tumorleiomyosarcoma rhabdomyosarcoma colon cancer colorectal cancer kidneycancer pancreatic cancer bone cancer breast cancer ovarian cancerprostate cancer esophogeal cancer stomach cancer oral cancer nasalcancer throat cancer squamous cell carcinoma basal cell carcinomaadenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillarycarcinoma papillary adenocarcinomas cystadenocarcinoma medullarycarcinoma bronchogenic carcinoma renal cell carcinoma hepatoma bile ductcarcinoma choriocarcinoma seminoma embryonal carcinoma Wilms' tumorcervical cancer uterine cancer testicular cancer small cell lungcarcinoma bladder carcinoma lung cancer epithelial carcinoma gliomaglioblastoma multiforme astrocytoma medulloblastoma craniopharyngiomaependymoma pinealoma hemangioblastoma acoustic neuroma oligodendrogliomameningioma skin cancer melanoma neuroblastoma retinoblastoma Blood-bornecancers, including but not limited to: acute lymphoblastic B-cellleukemia acute lymphoblastic T-cell leukemia acute myeloblastic leukemia“AML” acute promyelocytic leukemia “APL” acute monoblastic leukemiaacute erythroleukemic leukemia acute megakaryoblastic leukemia acutemyelomonocytic leukemia acute nonlymphocyctic leukemia acuteundifferentiated leukemia chronic myelocytic leukemia “CML” chroniclymphocytic leukemia “CLL” hairy cell leukemia multiple myeloma Acuteand chronic leukemias Lymphoblastic myelogenous lymphocytic myelocyticleukemias Lymphomas: Hodgkin's disease non-Hodgkin's Lymphoma Multiplemyeloma Waldenström's macroglobulinemia Heavy chain disease Polycythemiavera

Cancer, including, but not limited to, a tumor, metastasis, or anydisease or disorder characterized by uncontrolled cell growth, can betreated or prevented by administration of a Compound of the Invention.

5.2.8 Treatment of Other Diseases

The present invention provides methods for the treatment or preventionof Alzheimer's Disease, Syndrome X, septicemia, thrombotic disorders,obesity, pancreatitis, hypertension, inflammation, and impotence,comprising administering to a patient a therapeutically effective amountof a compound or a composition comprising a compound of the inventionand a pharmaceutically acceptable vehicle.

As used herein, “treatment or prevention of Alzheimer's Disease”encompasses treatment or prevention of lipoprotein abnormalitiesassociated with Alzheimer's Disease.

As used herein, “treatment or prevention of Syndrome X or MetabolicSyndrome” encompasses treatment or prevention of a symptom thereof,including but not limited to impaired glucose tolerance, hypertensionand dyslipidemia/dyslipoproteinemia.

As used herein, “treatment or prevention of septicemia” encompassestreatment or prevention of septic shock.

As used herein, “treatment or prevention of thrombotic disorders”encompasses treatment or prevention of high blood levels of fibrinogenand promotion of fibrinolysis.

In addition to treating or preventing obesity, the compositions of theinvention can be administered to an individual to promote weightreduction of the individual.

As used herein, “treatment or prevention of diabetic nephropathy”encompasses treating or preventing kidney disease that develops as aresult of diabetes mellitus (DM). Diabetes mellitus is a disorder inwhich the body is unable to metabolize carbohydrates (e.g., foodstarches, sugars, cellulose) properly. The disease is characterized byexcessive amounts of sugar in the blood (hyperglycemia) and urine;inadequate production and/or utilization of insulin; and by thirst,hunger, and loss of weight. Thus, the compounds of the invention canalso be used to treat or prevent diabetes mellitus.

As used herein, “treatment or prevention of diabetic retinopathy”encompasses treating or preventing complications of diabetes that leadto or cause blindness. Diabetic retinopathy occurs when diabetes damagesthe tiny blood vessels inside the retina, the light-sensitive tissue atthe back of the eye.

As used herein, “treatment or prevention of impotence” includes treatingor preventing erectile dysfunction, which encompasses the repeatedinability to get or keep an erection firm enough for sexual intercourse.The word “impotence” may also be used to describe other problems thatinterfere with sexual intercourse and reproduction, such as lack ofsexual desire and problems with ejaculation or orgasm. The term“treatment or prevention of impotence includes, but is not limited toimpotence that results as a result of damage to nerves, arteries, smoothmuscles, and fibrous tissues, or as a result of disease, such as, butnot limited to, diabetes, kidney disease, chronic alcoholism, multiplesclerosis, atherosclerosis, vascular disease, and neurologic disease.

As used herein, “treatment or prevention of hypertension” encompassestreating or preventing blood flow through the vessels at a greater thannormal force, which strains the heart; harms the arteries; and increasesthe risk of heart attack, stroke, and kidney problems. The termhypertension includes, but is not limited to, cardiovascular disease,essential hypertension, hyperpiesia, hyperpiesis, malignanthypertension, secondary hypertension, or white-coat hypertension.

As used herein, “treatment or prevention of inflammation” encompassestreating or preventing inflammation diseases including, but not limitedto, chronic inflammatory disorders of the joints including arthritis,e.g., rheumatoid arthritis and osteoarthritis; respiratory distresssyndrome, inflammatory bowel diseases such as ileitis, ulcerativecolitis and Crohn's disease; and inflammatory lung disorders such asasthma and chronic obstructive airway disease, inflammatory disorders ofthe eye such as corneal dystrophy, trachoma, onchocerciasis, uveitis,sympathetic ophthalmitis, and endophthalmitis; inflammatory disorders ofthe gum, e.g., periodontitis and gingivitis; tuberculosis; leprosy;inflammatory diseases of the kidney including glomerulonephritis andnephrosis; inflammatory disorders of the skin including acne,sclerodermatitis, psoriasis, eczema, photoaging and wrinkles;inflammatory diseases of the central nervous system, includingAIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer'sdisease, encephalomyelitis and viral or autoimmune encephalitis;autoimmune diseases including immune-complex vasculitis, systemic lupusand erythematodes; systemic lupus erythematosus (SLE); and inflammatorydiseases of the heart such as cardiomyopathy.

5.3 Combination Therapy

In certain embodiments of the present invention, the compounds andcompositions of the invention can be used in combination therapy with atleast one other therapeutic agent. The compound of the invention and thetherapeutic agent can act additively or, more preferably,synergistically. In a preferred embodiment, a compound or a compositioncomprising a compound of the invention is administered concurrently withthe administration of another therapeutic agent, which can be part ofthe same composition as the compound of the invention or a differentcomposition. In another embodiment, a compound or a compositioncomprising a compound of the invention is administered prior orsubsequent to administration of another therapeutic agent. As many ofthe disorders for which the compounds and compositions of the inventionare useful in treating are chronic disorders, in one embodimentcombination therapy involves alternating between administering acompound or a composition comprising a compound of the invention and acomposition comprising another therapeutic agent, e.g., to minimize thetoxicity associated with a particular drug. The duration ofadministration of each drug or therapeutic agent can be, e.g., onemonth, three months, six months, or a year. In certain embodiments, whena composition of the invention is administered concurrently with anothertherapeutic agent that potentially produces adverse side effectsincluding but not limited to toxicity, the therapeutic agent canadvantageously be administered at a dose that falls below the thresholdat which the adverse side is elicited.

The present compositions can be administered together with a statin.Statins for use in combination with the compounds and compositions ofthe invention include but are not limited to atorvastatin, pravastatin,fluvastatin, lovastatin, simvastatin, and cerivastatin.

The present compositions can also be administered together with a PPARagonist, for example a thiazolidinedione or a fibrate.Thiazolidinediones for use in combination with the compounds andcompositions of the invention include but are not limited to 5((4(2(methyl 2 pyridinylamino)ethoxy)phenyl)methyl) 2,4thiazolidinedione, troglitazone, pioglitazone, ciglitazone, WAY 120,744,englitazone, AD 5075, darglitazone, and rosiglitazone. Fibrates for usein combination with the compounds and compositions of the inventioninclude but are not limited to gemfibrozil, fenofibrate, clofibrate, orciprofibrate. As mentioned previously, a therapeutically effectiveamount of a fibrate or thiazolidinedione often has toxic side effects.Accordingly, in a preferred embodiment of the present invention, when acomposition of the invention is administered in combination with a PPARagonist, the dosage of the PPAR agonist is below that which isaccompanied by toxic side effects.

The present compositions can also be administered together with a bileacid binding resin. Bile acid binding resins for use in combination withthe compounds and compositions of the invention include but are notlimited to cholestyramine and colestipol hydrochloride. The presentcompositions can also be administered together with niacin or nicotinicacid. The present compositions can also be administered together with aRXR agonist. RXR agonists for use in combination with the compounds ofthe invention include but are not limited to LG 100268, LGD 1069, 9-cisretinoic acid, 2(1(3,5,5,8,8 pentamethyl 5,6,7,8 tetrahydro 2naphthyl)cyclopropyl)pyridine 5 carboxylic acid, or 4((3,5,5,8,8pentamethyl 5,6,7,8 tetrahydro 2 naphthyl)2 carbonyl)benzoic acid. Thepresent compositions can also be administered together with ananti-obesity drug. Anti-obesity drugs for use in combination with thecompounds of the invention include but are not limited to β-adrenergicreceptor agonists, preferably β-3 receptor agonists, fenfluramine,dexfenfluramine, sibutramine, bupropion, fluoxetine, and phentermine.The present compositions can also be administered together with ahormone. Hormones for use in combination with the compounds of theinvention include but are not limited to thyroid hormone, estrogen andinsulin. Preferred insulins include but are not limited to injectableinsulin, transdermal insulin, inhaled insulin, or any combinationthereof. As an alternative to insulin, an insulin derivative,secretagogue, sensitizer or mimetic may be used. Insulin secretagoguesfor use in combination with the compounds of the invention include butare not limited to forskolin, dibutryl cAMP or isobutylmethylxanthine(IBMX).

The present compositions can also be administered together with aphosphodiesterase type 5 (“PDE5”) inhibitor to treat or preventdisorders, such as but not limited to, impotence. In a particular,embodiment the combination is a synergistic combination of a compositionof the invention and a PDE5 inhibitor.

The present compositions can also be administered together with atyrophostine or an analog thereof. Tyrophostines for use in combinationwith the compounds of the invention include but are not limited totryophostine 51.

The present compositions can also be administered together withsulfonylurea-based drugs. Sulfonylurea-based drugs for use incombination with the compounds of the invention include, but are notlimited to, glisoxepid, glyburide, acetohexamide, chlorpropamide,glibornuride, tolbutamide, tolazamide, glipizide, gliclazide,gliquidone, glyhexamide, phenbutamide, and tolcyclamide. The presentcompositions can also be administered together with a biguanide.Biguanides for use in combination with the compounds of the inventioninclude but are not limited to metformin, phenformin and buformin.

The present compositions can also be administered together with anα-glucosidase inhibitor. α-glucosidase inhibitors for use in combinationwith the compounds of the invention include but are not limited toacarbose and miglitol.

The present compositions can also be administered together with an apoA-I agonist. In one embodiment, the apo A-I agonist is the Milano formof apo A-I (apo A-IM). In a preferred mode of the embodiment, the apoA-IM for administration in conjunction with the compounds of theinvention is produced by the method of U.S. Pat. No. 5,721,114 toAbrahamsen. In a more preferred embodiment, the apo A-I agonist is apeptide agonist. In a preferred mode of the embodiment, the apo A-Ipeptide agonist for administration in conjunction with the compounds ofthe invention is a peptide of U.S. Pat. No. 6,004,925 or U.S. Pat. No.6,037,323 to Dasseux.

The present compositions can also be administered together withapolipoprotein E (apo E). In a preferred mode of the embodiment, theapoE for administration in conjunction with the compounds of theinvention is produced by the method of U.S. Pat. No. 5,834,596 toAgeland.

In yet other embodiments, the present compositions can be administeredtogether with an HDL-raising drug; an HDL enhancer; or a regulator ofthe apolipoprotein A-I, apolipoprotein A-IV and/or apolipoprotein genes.

In one embodiment, the other therapeutic agent can be an antiemeticagent. Suitable antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine,thioproperazine and tropisetron.

In another embodiment, the other therapeutic agent can be anhematopoietic colony stimulating factor. Suitable hematopoietic colonystimulating factors include, but are not limited to, filgrastim,sargramostim, molgramostim and erythropoietin alfa.

In still another embodiment, the other therapeutic agent can be anopioid or non-opioid analgesic agent. Suitable opioid analgesic agentsinclude, but are not limited to, morphine, heroin, hydromorphone,hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine,etorphine, buprenorphine, meperidine, lopermide, anileridine,ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil,sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan,phenazocine, pentazocine, cyclazocine, methadone, isomethadone andpropoxyphene. Suitable non-opioid analgesic agents include, but are notlimited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal,etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin,ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen,piroxicam and sulindac.

5.3.1 Combination Therapy of Cardiovascular Diseases

The present compositions can be administered together with a knowncardiovascular drug. Cardiovascular drugs for use in combination withthe compounds of the invention to prevent or treat cardiovasculardiseases include but are not limited to peripheral antiadrenergic drugs,centrally acting antihypertensive drugs (e.g., methyldopa, methyldopaHCl), antihypertensive direct vasodilators (e.g., diazoxide, hydralazineHCl), drugs affecting renin-angiotensin system, peripheral vasodilators,phentolamine, antianginal drugs, cardiac glycosides, inodilators (e.g.,aminone, milrinone, enoximone, fenoximone, imazodan, sulmazole),antidysrhythmic drugs, calcium entry blockers, ranitine, bosentan, andrezulin.

5.3.2 Combination Therapy of Cancer

The present invention includes methods for treating cancer, comprisingadministering to an animal in need thereof an effective amount of aCompound of the Invention and another therapeutic agent that is ananti-cancer agent. Suitable anticancer agents include, but are notlimited to, those listed in Table 3.

TABLE 3 Alkylating agents Nitrogen mustards: Cyclophosphamide Ifosfamidetrofosfamide Chlorambucil Treos Nitrosoureas: carbustine (BCNU)Lomustine (CCNU) Alkylsulphonates Busulfan Treosulfan Triazenes:Dacarbazine Platinum containing compounds: Cisplatin carboplatin PlantAlkaloids Vinca alkaloids: Vicristine Vinblastine Vindesine VinorelbineTaxoids: paclitaxel Docetaxol DNA Topoisomerase InhibitorsEpipodophyllins: Etoposide Teniposide Topotecan 9-aminocamptothecincamptothecin crisnatol mitomycins: Mitomycin C Anti-metabolitesAnti-folates: DHFR inhibitors: METHOTREXATE Trimetrexate IMPdehydrogenase Inhibitors: Mycophenolic acid Tiazofurin Ribavirin EICARRibonuclotide reductase Inhibitors: Hydroxyurea deferoxamine Pyrimidineanalogs: Uracil analogs 5-Fluorouracil Floxuridine DoxifluridineRatitrexed Cytosine analogs cytarabine (ara C) Cytosine arabinosidefludarabine Purine analogs: mercaptopurine Thioguanine Hormonaltherapies: Receptor antagonists: Anti-estrogen Tamoxifen Raloxifenemegestrol goscrclin Leuprolide acetate LHRH agonists: flutamidebicalutamide Retinoids/Deltoids Vitamin D3 analogs: EB 1089 CB 1093 KH1060 Photodynamic therapies: vertoporfin (BPD-MA) Phthalocyaninephotosensitizer Pc4 Demethoxy-hypocrellin A (2BA-2-DMHA) Cytokines:Interferon-α Interferon-γ Tumor necrosis factor Others: Isoprenylationinhibitors: Lovastatin Dopaminergic neurotoxins: 1-methyl-4-phenylpyridinium ion Cell cycle inhibitors: staurosporine Actinomycines:Actinomycin D Dactinomycin Bleomycins: bleomycin A2 Bleomycin B2Peplomycin Anthracyclines: daunorubicin Doxorubicin (adriamycin)Idarubicin Epirubicin Pirarubicin Zorubicin Mitoxantrone MDR inhibitorsverapamil Ca²⁺ATPase inhibitors: thapsigargin

In a specific embodiment, a composition of the invention furthercomprises one or more chemotherapeutic agents and/or is administeredconcurrently with radiation therapy. In another specific embodiment,chemotherapy or radiation therapy is administered prior or subsequent toadministration of a present composition, preferably at least an hour,five hours, 12 hours, a day, a week, a month, more preferably severalmonths (e.g., up to three months), subsequent to administration of acomposition of the invention.

In other embodiments, the invention provides methods for treating orpreventing cancer, comprising administering to an animal in need thereofan effective amount of a Compound of the Invention and achemotherapeutic agent. In one embodiment the chemotherapeutic agent isthat with which treatment of the cancer has not been found to berefractory. In another embodiment, the chemotherapeutic agent is thatwith which the treatment of cancer has been found to be refractory. TheCompounds of the Invention can be administered to an animal that hasalso undergone surgery as treatment for the cancer.

In one embodiment, the additional method of treatment is radiationtherapy.

In a specific embodiment, the Compound of the Invention is administeredconcurrently with the chemotherapeutic agent or with radiation therapy.In another specific embodiment, the chemotherapeutic agent or radiationtherapy is administered prior or subsequent to administration of aCompound of the Invention, preferably at least an hour, five hours, 12hours, a day, a week, a month, more preferably several months (e.g., upto three months), prior or subsequent to administration of a Compound ofthe Invention.

A chemotherapeutic agent can be administered over a series of sessions,any one or a combination of the chemotherapeutic agents listed in Table3 can be administered. With respect to radiation, any radiation therapyprotocol can be used depending upon the type of cancer to be treated.For example, but not by way of limitation, x-ray radiation can beadministered; in particular, high-energy megavoltage (radiation ofgreater that 1 MeV energy) can be used for deep tumors, and electronbeam and orthovoltage x-ray radiation can be used for skin cancers.Gamma-ray emitting radioisotopes, such as radioactive isotopes ofradium, cobalt and other elements, can also be administered.

Additionally, the invention provides methods of treatment of cancer witha Compound of the Invention as an alternative to chemotherapy orradiation therapy where the chemotherapy or the radiation therapy hasproven or can prove too toxic, e.g., results in unacceptable orunbearable side effects, for the subject being treated. The animal beingtreated can, optionally, be treated with another cancer treatment suchas surgery, radiation therapy or chemotherapy, depending on whichtreatment is found to be acceptable or bearable.

The Compounds of the Invention can also be used in an in vitro or exvivo fashion, such as for the treatment of certain cancers, including,but not limited to leukemias and lymphomas, such treatment involvingautologous stem cell transplants. This can involve a multi-step processin which the animal's autologous hematopoietic stem cells are harvestedand purged of all cancer cells, the patient's remaining bone-marrow cellpopulation is then eradicated via the administration of a high dose of aCompound of the Invention with or without accompanying high doseradiation therapy, and the stem cell graft is infused back into theanimal. Supportive care is then provided while bone marrow function isrestored and the animal recovers.

5.4 Surgical Uses

Cardiovascular diseases such as atherosclerosis often require surgicalprocedures such as angioplasty. Angioplasty is often accompanied by theplacement of a reinforcing a metallic tube shaped structure known as a“stent” into a damaged coronary artery. For more serious conditions,open heart surgery such as coronary bypass surgery may be required.These surgical procedures entail using invasive surgical devices and/orimplants, and are associated with a high risk of restenosis andthrombosis. Accordingly, the compounds and compositions of the inventionmay be used as coatings on surgical devices (e.g., catheters) andimplants (e.g., stents) to reduce the risk of restenosis and thrombosisassociated with invasive procedures used in the treatment ofcardiovascular diseases.

5.5 Veterinary and Livestock Uses

A composition of the invention can be administered to a non-human animalfor a veterinary use for treating or preventing a disease or disorderdisclosed herein.

In a specific embodiment, the non-human animal is a household pet. Inanother specific embodiment, the non-human animal is a livestock animal.In a preferred embodiment, the non-human animal is a mammal, mostpreferably a cow, horse, sheep, pig, cat, dog, mouse, rat, rabbit, orguinea pig. In another preferred embodiment, the non-human animal is afowl species, most preferably a chicken, turkey, duck, goose, or quail.

In addition to veterinary uses, the compounds and compositions of theinvention can be used to reduce the fat content of livestock to produceleaner meats. Alternatively, the compounds and compositions of theinvention can be used to reduce the cholesterol content of eggs byadministering the compounds to a chicken, quail, or duck hen. Fornon-human animal uses, the compounds and compositions of the inventioncan be administered via the animals' feed or orally as a drenchcomposition.

5.6 Therapeutic/Prophylactic Administration and Compositions

Due to the activity of the compounds and compositions of the invention,they are useful in veterinary and human medicine. As described above,the compounds and compositions of the invention are useful for thetreatment or prevention of aging, Alzheimer's Disease, cancer,cardiovascular disease, diabetic nephropathy, diabetic retinopathy, adisorder of glucose metabolism, dyslipidemia, dyslipoproteinemia,hypertension, impotence, inflammation, insulin resistance, lipidelimination in bile, modulating C reactive protein, obesity, oxysterolelimination in bile, pancreatitis, Parkinson's disease, a peroxisomeproliferator activated receptor-associated disorder, phospholipidelimination in bile, renal disease, septicemia, metabolic syndromedisorders (e.g., Syndrome X), a thrombotic disorder, enhancing bileproduction, enhancing reverse lipid transport, inflammatory processesand diseases like gastrointestinal disease, irritable bowel syndrome(IBS), inflammatory bowel disease (e.g., Crohn's Disease, ulcerativecolitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis),autoimmune disease (e.g., systemic lupus erythematosus), scleroderma,ankylosing spondylitis, gout and pseudogout, muscle pain:polymyositis/polymyalgia rheumatica/fibrositis; infection and arthritis,juvenile rheumatoid arthritis, tendonitis, bursitis and other softtissue rheumatism.

The invention provides methods of treatment and prophylaxis byadministration to a patient of a therapeutically effective amount of acompound or a composition comprising a compound of the invention. Thepatient is an animal, including, but not limited, to an animal such acow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat,rabbit, guinea pig, etc., and is more preferably a mammal, and mostpreferably a human.

The compounds and compositions of the invention, are preferablyadministered orally. The compounds and compositions of the invention mayalso be administered by any other convenient route, for example, byintravenous infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal andintestinal mucosa, etc.) and may be administered together with anotherbiologically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc., and can be used toadminister a compound of the invention. In certain embodiments, morethan one compound of the invention is administered to a patient. Methodsof administration include but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. The preferred mode of administration is leftto the discretion of the practitioner, and will depend in-part upon thesite of the medical condition. In most instances, administration willresult in the release of the compounds of the invention into thebloodstream.

In specific embodiments, it may be desirable to administer one or morecompounds of the invention locally to the area in need of treatment.This may be achieved, for example, and not by way of limitation, bylocal infusion during surgery, topical application, e.g., in conjunctionwith a wound dressing after surgery, by injection, by means of acatheter, by means of a suppository, or by means of an implant, saidimplant being of a porous, non-porous, or gelatinous material, includingmembranes, such as sialastic membranes, or fibers. In one embodiment,administration can be by direct injection at the site (or former site)of an atherosclerotic plaque tissue.

In certain embodiments, for example, for the treatment of Alzheimer'sDisease, it may be desirable to introduce one or more compounds of theinvention into the central nervous system by any suitable route,including intraventricular, intrathecal and epidural injection.Intraventricular injection may be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of the invention can be formulated asa suppository, with traditional binders and vehicles such astriglycerides.

In another embodiment, the compounds and compositions of the inventioncan be delivered in a vesicle, in particular a liposome (see Langer,1990, Science 249:1527 1533; Treat et al., in Liposomes in the Therapyof Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.),Liss, New York, pp. 353 365 (1989); Lopez Berestein, ibid., pp. 317 327;see generally ibid.).

In yet another embodiment, the compounds and compositions of theinvention can be delivered in a controlled release system. In oneembodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRCCrit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507Saudek et al., 1989, N. Engl. J. Med. 321:574). In another embodiment,polymeric materials can be used (see Medical Applications of ControlledRelease, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974);Controlled Drug Bioavailability, Drug Product Design and Performance,Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983,J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al.,1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howardet al., 1989, J. Neurosurg. 71:105). In yet another embodiment, acontrolled-release system can be placed in proximity of the target areato be treated, e.g., the liver, thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, in Medical Applications of ControlledRelease, supra, vol. 2, pp. 115 138 (1984)). Other controlled-releasesystems discussed in the review by Langer, 1990, Science 249:1527 1533)may be used.

The present compositions will contain a therapeutically effective amountof a compound of the invention, optionally more than one compound of theinvention, preferably in purified form, together with a suitable amountof a pharmaceutically acceptable vehicle so as to provide the form forproper administration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “vehicle” refers to a diluent, adjuvant, excipient, or carrier withwhich a compound of the invention is administered. Such pharmaceuticalvehicles can be liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The pharmaceuticalvehicles can be saline, gum acacia, gelatin, starch paste, talc,keratin, colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.When administered to a patient, the compounds and compositions of theinvention and pharmaceutically acceptable vehicles are preferablysterile. Water is a preferred vehicle when the compound of the inventionis administered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in “Remington's PharmaceuticalSciences” by E. W. Martin.

In a preferred embodiment, the compounds and compositions of theinvention are formulated in accordance with routine procedures as apharmaceutical composition adapted for intravenous administration tohuman beings. Typically, compounds and compositions of the invention forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the compositions may also include asolubilizing agent. Compositions for intravenous administration mayoptionally include a local anesthetic such as lignocaine to ease pain atthe site of the injection. Generally, the ingredients are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the compound of the invention is to beadministered by intravenous infusion, it can be dispensed, for example,with an infusion bottle containing sterile pharmaceutical grade water orsaline. Where the compound of the invention is administered byinjection, an ampoule of sterile water for injection or saline can beprovided so that the ingredients may be mixed prior to administration.

Compounds and compositions of the invention for oral delivery may be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs. Compounds andcompositions of the invention for oral delivery can also be formulatedin foods and food mixes. Orally administered compositions may containone or more optionally agents, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,to provide a pharmaceutically palatable preparation. Moreover, where intablet or pill form, the compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds andcompositions of the invention. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed in the compositions will also depend on theroute of administration, and the seriousness of the disease or disorder,and should be decided according to the judgment of the practitioner andeach patient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.001 milligram to 2000 milligrams ofa compound of the invention per kilogram body weight. In specificpreferred embodiments of the invention, the oral dose is 0.01 milligramto 1000 milligrams per kilogram body weight, more preferably 0.1milligram to 100 milligrams per kilogram body weight, more preferably0.5 milligram to 25 milligrams per kilogram body weight, and yet morepreferably 1 milligram to 10 milligrams per kilogram body weight. In amost preferred embodiment, the oral dose is 5 milligrams of a compoundof the invention per kilogram body weight. The dosage amounts describedherein refer to total amounts administered; that is, if more than onecompound of the invention is administered, the preferred dosagescorrespond to the total amount of the compounds of the inventionadministered. Oral compositions preferably contain 10% to 95% activeingredient by weight.

Suitable dosage ranges for intravenous (i.v.) administration are 0.01milligram to 1000 milligrams per kilogram body weight, 0.1 milligram to350 milligrams per kilogram body weight, and 1 milligram to 100milligrams per kilogram body weight. Suitable dosage ranges forintranasal administration are generally about 0.01 pg/kg body weight to1 mg/kg body weight. Suppositories generally contain 0.01 milligram to50 milligrams of a compound of the invention per kilogram body weightand comprise active ingredient in the range of 0.5% to 10% by weight.Recommended dosages for intradermal, intramuscular, intraperitoneal,subcutaneous, epidural, sublingual, intracerebral, intravaginal,transdermal administration or administration by inhalation are in therange of 0.001 milligram to 200 milligrams per kilogram of body weight.Suitable doses of the compounds of the invention for topicaladministration are in the range of 0.001 milligram to 1 milligram,depending on the area to which the compound is administered. Effectivedoses may be extrapolated from dose-response curves derived from invitro or animal model test systems. Such animal models and systems arewell known in the art.

The invention also provides pharmaceutical packs or kits comprising oneor more containers filled with one or more compounds of the invention.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration. In a certain embodiment, the kit contains more than onecompound of the invention. In another embodiment, the kit comprises acompound of the invention and another lipid-mediating compound,including but not limited to a statin, a thiazolidinedione, or afibrate.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetheradministration of a specific compound of the invention or a combinationof compounds of the invention is preferred for lowering fatty acidsynthesis. The compounds and compositions of the invention may also bedemonstrated to be effective and safe using animal model systems.

Other methods will be known to the skilled artisan and are within thescope of the invention.

The following examples are provided by way of illustration and notlimitation.

6. SYNTHETIC EXAMPLES

6.1 Tert-Butyl 1-(4-bromo-butyl)-cyclopropanecarboxylate

Under a N₂ atmosphere at −60° C., a solution of tert-butylcyclopropanecarboxylate (80.05 g, 0.507 mol) and 1,4-dibromobutane(219.3 g, 1.01 mol) in dry THF (800 mL) was added drop wise to asolution of LDA (2 M in THF/heptane/ethylbenzene, 380 mL, 0.76 mol) in1.5 h. Stirring was continued for 5 h, during which the reaction mixturewas allowed to slowly reach rt. After that, the reaction mixture waspoured into saturated aqueous NH₄Cl (1 L). The organic layer wasseparated and concentrated in vacuo to a smaller volume. The aqueouslayer was extracted with Et₂O (3×200 mL). The combined organic layerswere washed with saturated aqueous NH₄Cl (2×400 mL) and brine (400 mL),dried (Na₂SO₄) and evaporated in vacuo. The remaining residue waspurified by fractional distillation under reduced pressure to givetert-Butyl 1-(4-bromo-butyl)-cyclopropanecarboxylate (51.4 g, 94% pureby GC, 34%) as a slightly yellow oil. bp: T=93-96° C. (p=0.075-0.087Torr), ¹H NMR (CDCl₃): δ=3.40 (t, J=6.8 Hz, 2H), 1.85 (quintet, J=7.1Hz, 2H), 1.65-1.46 (m, 4H), 1.43 (s, 9H), 1.12 (q, J=3.5 Hz, 2H), 0.60(q, J=3.5 Hz, 2H). ¹³C NMR (CDCl₃): δ=174.0, 79.8, 33.6, 33.2, 32.8,27.9 (3×), 26.3, 23.9, 15.1 (2×). HRMS calcd for C₁₂H₂₁BrO₂ (MH⁺):277.0803. found: 277.0807.

6.2 Tert-butyl1-[9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-oxononyl]-1-cyclopropanecarboxylate

Under a N₂ atmosphere, NaH (60% (^(W)/_(W)) in mineral oil, 2.91 g, 72.8mmol) was added portion wise to a solution of TosMIC (5.85 g, 30.0 mmol)and Bu₄NI (1.10 g, 2.98 mmol) in dry DMSO (100 mL) while stirringvigorously and cooling with a water bath. After 10 min, tert-Butyl1-(4-bromo-butyl)-cyclopropanecarboxylate (16.56 g, 94% pure by GC, 56.2mmol) was added drop wise in 20 min and stirring was continued for 1 hand 50 min. Then, H₂O (100 mL) was added drop wise and the resultingmixture was extracted with Et₂O (3×100 mL). The combined organic layerswere washed with brine (2×100 mL), dried (Na₂SO₄) and evaporated invacuo. The remaining oil was purified by column chromatography (silica,heptane:EtOAc=6:1) to give tert-butyl1-{9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl}-1-cyclopropanecarboxylate(10.00 g) as a slightly yellow oil. The above mentioned oil (10.00 g)was dissolved in CH₂Cl₂ (200 mL) and conc aqueous HCl (4 mL) was added.After stirring vigorously for 1 h, H₂O (100 mL) was added and the layerswere separated. The aqueous phase was extracted with CH₂Cl₂ (100 mL) andthe combined organic layers were washed with saturated aqueous NaHCO₃(3×100 mL), dried (Na₂SO₄) and evaporated in vacuo. The remainingresidue was purified by column chromatography (silica,heptane:EtOAc=10:1) to give tert-butyl1-[9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-oxononyl]-1-cyclopropanecarboxylate(5.80 g, 49%) as a colorless oil. ¹H NMR (CDCl₃): δ=2.39 (t, J=7.3 Hz,4H), 1.63-1.38 (m, 30H), 1.10 (dd, J=6.6, 3.9 Hz, 4H), 0.59 (dd, J=6.7,3.9 Hz, 4H). ¹³C NMR (CDCl₃): δ=211.1, 174.4 (2×), 79.9 (2×), 42.7 (2×),33.9 (2×), 28.0 (6×), 27.4 (2×), 24.1 (2×), 24.0 (2×), 15.2 (4×). HRMScalcd for C₂₅H₄₃O₅ (MH⁺): 423.3111. found: 423.3111.

6.3 1-[9-(1-Carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylicacid

A solution of tert-butyl1-[9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-oxononyl]-1-cyclopropanecarboxylate(5.31 g, 12.6 mmol) in HCO₂H (50 mL) was stirred for 3 h, evaporated invacuo and coevaporated from toluene (3×25 mL) to give1-[9-(1-carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylic acid(3.89 g, 99%) as a white solid. An analytical sample was obtained afterrecrystallization from iPr₂O/heptane. mp: 132-134° C. ¹H NMR (CD₃OD):δ=2.45 (t, J=6.9 Hz, 4H), 1.58-1.39 (m, 12H), 1.14 (dd, J=6.6, 3.7 Hz,4H), 0.70 (dd, J=6.8, 3.9 Hz, 4H). ¹³C NMR (CD₃OD): δ=214.4, 179.4 (2×),43.5 (2×), 34.9 (2×), 28.5 (2×), 25.1 (2×), 24.2 (2×), 16.2 (4×). Anal.calcd for C₁₇H₂₆O₅: C, 65.78; H, 8.44. found: C, 65.40; H, 8.37.

6.4 1-[9-(1-Carboxycyclopropyl)-5-hydroxynonyl]-1-cyclopropanecarboxylicacid

To a suspension of1-[9-(1-carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylic acid(6.95 g, 22.4 mmol) in iPrOH (40 mL) and H₂O (40 mL) was added NaOH(1.80 g, 45.0 mmol). After 30 min of stirring, NaBH₄ (0.45 g, 11.8 mmol)was added to the resulting clear solution. After 3 h and 15 min, themixture was acidified to pH˜1 with aqueous HCl (1M) and extracted withEt₂O (3×100 mL). The combined organic phases were dried (Na₂SO₄) andevaporated in vacuo to give1-[9-(1-carboxycyclopropyl)-5-hydroxynonyl]-1-cyclopropanecarboxylicacid (6.02 g, 86%) as a slightly yellow oil. ¹H NMR (CD₃OD): δ=3.49 (brs, 1H), 1.57-1.25 (m, 16H), 1.14 (dd, J=3.6, 6.3, 4H), 0.70 (dd, J=3.3,6.3, 4H). ¹³C NMR (CD₃OD): δ=178.9 (2×), 72.2, 38.4 (2×), 35.1 (2×),28.9 (2×), 27.0 (2×), 24.3 (2×), 16.3 (2×), 16.2 (2×).

6.5 Tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate

Under an Ar atmosphere at 0° C., BuLi (2.5M in hexanes, 80 mL, 0.20 mol)was added dropwise to a solution of iPr₂NH (27.2 mL, 194 mmol, distilledfrom NaOH) in dry THF (200 mL) in 30 min. The reaction mixture wasstirred for 30 min, cooled to −70° C. and then, tert-butylcyclopropanecarboxylate (prepared according to Kohlrausch, K. W. F.;Skrabal, R., Z. Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285, 25.0g, 176 mmol) was added dropwise in 30 min. The resultant mixture wasallowed to warm up to −35° C., cooled again to −70° C. and then1-bromo-5-chloropentane (36 mL, 50.7 g, 273 mmol) was added dropwise in15 min. The reaction mixture was allowed to reach −5° C., stirred for 3h, poured into a mixture of ice (100 mL), H₂O (100 mL), brine (200 mL)and aqueous HCl (2M, 200 mL) and extracted with Et₂O (2×300 mL). Thecombined organic layers were washed with a mixture of brine andsaturated aqueous NaHCO₃ (10:1, 300 mL), dried (Na₂SO₄) and evaporatedin vacuo. The remaining oil was purified by fractional distillationunder reduced pressure to give tert-butyl1-(5-chloropentyl)-1-cyclopropanecarboxylate (31.5 g 73%) as a colorlessliquid. bp: T=67-74° C. (p=0.001 mbar). ¹H NMR (CDCl₃): δ=3.52 (t, J=6.6Hz, 2H), 1.77 (quintet, J=6.8 Hz, 2H), 1.48-1.38 (m, 6H), 1.42 (s, 9H),1.10 (dd, J=6.5 Hz, 3.8 Hz, 2H), 0.59 (dd, J=6.6, 3.9 Hz, 21). ¹³C NMR(CDCl₃): δ=174.1, 79.9, 45.2, 34.2, 32.7, 28.2 (3×), 27.20, 27.17, 24.3,15.4 (2×). HRMS calcd for C₁₃H₂₄ClO₂ (MH⁺): 247.1465. found: 247.1465.

6.6 Tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate

To a solution of tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate(31.5 g, 128 mmol) in 2-butanone (150 mL) was added NaI (24.9 g, 166mmol). The reaction mixture was stirred under reflux for 24 h, dilutedwith heptane (220 mL) and filtered through a layer of silica 2 cm) in aglassfilter. The residue was eluted with a mixture of heptane and EtOAc(3:1, 5×100 mL). The combined filtrate and elutes were evaporated invacuo to give tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate(42.3 g, 99%) as a slightly yellow liquid. ¹H NMR (CDCl₃): δ=3.18 (t,J=7.1 Hz, 2H), 1.82 (quintet, J=7.1 Hz, 2H), 1.48-1.33 (m, 6H), 1.42 (s,9H), 1.10 (dd, J=6.8 Hz, Hz, 2H), 0.58 (dd, J=6.6, 3.9 Hz, 2H). ¹³C NMR(CDCl₃): δ=174.0, 79.9, 34.1, 33.6, 30.8, 28.2 (3×), 26.8, 24.3, 15.4(2×), 7.4. HRMS calcd for C₁₃H₂₃IO₂ (M⁺): 338.0743. found: 338.0743.

6.7 Tert-butyl1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-oxoundecyl-1-cyclopropanecarboxylate

Under a N₂ atmosphere at 0° C., KOtBu (8.35 g, 74.6 mmol) was added to asolution of TosMIC (13.84 g, 70.9 mmol) in DMAc (100 mL). Thentert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (24.0 g, 71.0mmol) was added dropwise in 15 min and the reaction mixture was allowedto warm to rt, stirred for 0.5 h and cooled again to 0° C. Anotherportion of KOtBu (8.35 g, 74.6 mmol) and tert-butyl1-(5-iodopentyl)-1-cyclopropanecarboxylate (24 g, 71 mmol, in 15 min)were added and the resultant mixture was allowed to warm to rt. After 2h, the reaction mixture was poured into an ice/H₂O (300 mL) mixture andextracted with Et₂O (3×150 mL). To the combined organic layers was addedEtOAc (100 mL) and the resultant solution was washed with a mixture ofbrine (100 mL), H₂O (100 mL) and aqueous Na₂SO₃ (10%, 50 mL), dried(Na₂SO₄) and evaporated in vacuo. The remaining residue was taken up inEtOAc (100 mL) and filtered through a layer of silica in a glassfilter(elute: heptane:EtOAc=1:1, 5×80 mL). The combined filtrate and washingswere evaporated in vacuo. The remaining oil was dissolved in CH₂Cl₂ (400mL) and conc aqueous HCl (11.4 mL) was added. After 0.5 h, the reactionmixture was treated with saturated aqueous NaHCO₃ (250 mL) and stirredfor 0.5 h. The layers were separated and the aqueous phase was extractedwith CH₂Cl₂ (200 mL). The combined organic layers were dried (Na₂SO₄)and evaporated in vacuo. The remaining residue was dissolved in heptaneand set aside for 3 d upon which precipitation occurred. The residue wasseparated by decantation and washed with heptane (3×75 mL). The combinedheptane layers were evaporated in vacuo and the resultant oil waspurified by column chromatography (silica, heptane:EtOAc=12:1) to givetert-butyl1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-oxoundecyl-1-cyclopropanecarboxylate(16.3 g, >90% pure by ¹H NMR, 46%) as a colorless oil. ¹H NMR (CDCl₃):δ=2.37 (t, J=7.4 Hz, 4H), 1.62-1.49 (quintet, J=7.4 Hz, 4H), 1.48-1.36(m, 8H), 1.41 (s, 18H), 1.33-1.20 (m, 4H) 1.09 (dd, J=6.5, 3.8 Hz, 4H),0.58 (dd, J=6.6, 3.9 Hz, 4H). ¹³C NMR (CDCl₃): δ=210.9, 174.1 (2×), 79.8(2×), 42.9 (2×), 34.1 (2×), 29.6 (2×), 28.2 (6×), 27.7 (2×), 24.4 (2×),24.0 (2×), 15.4 (4×). HRMS calcd for C₂₇H₄₆O₅Na (MNa⁺): 473.3243. found473.3233.

6.8 Tert-butyl1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-hydroxyundecyl-1-cyclopropanecarboxylate

A solution of tert-butyl1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-oxoundecyl-1-cyclopropanecarboxylate(7.87 g, 17.4 mmol) in EtOH (40 mL) was treated portion wise with NaBH₄(0.726 g, 19.2 mmol) in ˜2 min at 0° C. The reaction mixture was stirredat rt for 1.5 h, and then poured into a mixture of H₂O and ice (200 mL).The resultant mixture was extracted with Et₂O (2×200 mL), and thecombined organic layers were dried (Na₂SO₄) and concentrated in vacuo.The remaining residue was purified by column chromatography (silica,heptane:EtOAc=8:1) to give tert-butyl1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-hydroxyundecyl-1-cyclopropanecarboxylate(7.00 g, 89%) as a colorless oil. ¹H NMR (CDCl₃) δ=3.61-3.51 (m, 1H),1.49-1.21 (m, 39H) 1.09 (dd, J=6.5, 3.8 Hz, 4H), 0.58 (dd, J=6.5, 3.8Hz, 4H). ¹³C NMR (CDCl₃) δ=174.2 (2×), 79.7 (2×), 71.9, 37.6 (2×), 34.2(2×), 30.0 (2×), 28.2 (6×), 27.9 (2×), 25.8 (2×), 24.4 (2×), 15.4 (2×),15.3 (2×). HRMS calcd for C₂₇H₄₉O₅ (M+H)⁺: 453.3580. found 453.3550.

6.91-[11-(1-Carboxycyclopropyl)-6-hydroxyundecyl]-1-cyclopropanecarboxylicacid

A solution of tert-butyl1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-hydroxyundecyl-1-cyclopropanecarboxylate(6.49 g, 14.4 mmol) in 1,4-dioxane (70 mL) was treated with cone HCl (70mL) and stirred overnight. Then the mixture was treated with a mixtureof ice and H₂O (1:1, 300 mL), and extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (3×100 mL), dried(Na₂SO₄), and concentrated in vacuo. The remaining oil was coevaporatedin vacuo from toluene (2×50 mL), CH₂Cl₂ (50 mL) and Et₂O (3×50 mL), andfinally further concentrated in vacuo at 65° C. for 3 h, to give1-[11-(1-carboxycyclopropyl)-6-hydroxyundecyl]-1-cyclopropane-carboxylicacid (5.08 g, 100%) as a slightly yellow oil, contaminated with Et₂O (4%(^(W)/_(W))) and toluene (0.5% (^(W)/_(W))). The thick oil started tocrystallize spontaneously after 10 d, after which H₂O (100 mL) wasadded. The resulting mixture was left standing for 3 d, and the soobtained crystalline material was filtered and air dried to give1-[11-(1-carboxycyclopropyl)-6-hydroxyundecyl]-1-cyclopropanecarboxylicacid (4.64 g, 95%) as colorless crystals. mp: 87-91° C. ¹H NMR (CDCl₃)δ=5.50 (br s, 3H), 3.58, (br s, 1H), 1.53-1.22 (m, 20H) 1.25 (dd, J=6.6,3.9 Hz, 4H), 0.74 (dd, J=6.9, 3.9 Hz, 4H). ¹³C NMR (CDCl₃) δ=181.6 (2×),72.0, 37.3 (2×), 33.7 (2×), 29.9 (2×), 27.6 (2×), 25.6 (2×), 23.5 (2×),16.7 (2×), 16.6 (2×). Anal. calcd for C₁₉H₃₂O₅: C, 67.03; H, 9.47.Found: C, 66.83; H, 9.24.

6.10{7-Ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne)ammonium

To a mixture of K₂CO₃ (13.18 g, 95.6 mmol) and Bu₄NI (2.35 g, 6.36 mmol)in dry DMF (50 mL) was added a solution of ethyl2,2-dimethyl-6-bromohexanoate (prepared according to Ackerley, N.;Brewster, A. G.; Brown, G. R.; Clarke, D. S.; Foubister, A. J., Griffin,S. J.; Hudson, J. A.; Smithers, M. J.; Whittamore, P. R. O., J. Med.Chem., 1995, 38, 1608-1628, 24.00 g, 95.6 mmol) and TosMIC (12.41 g,63.7 mmol) in dry DMF (50 mL) in 20 min under a N₂ atmosphere whilestirring vigorously. After 4 d, H₂O (100 mL) was added drop wise whilekeeping the temperature below 25° C. by cooling with an ice-bath. Theresulting mixture was extracted with Et₂O (3×200 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃ (2×200 mL),dried (Na₂SO₄), and evaporated in vacuo. The remaining residue waspurified by column chromatography (silica; heptane:EtOAc=6:1; a layer ofNaHCO₃ was put on the base of the column) to give{7-ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne)ammonium (15.68 g, 42.8 mmol, 67%) as a slightly yellow oil which slowlysolidified on standing. An analytical sample was obtained afterrecrystallization (0.43 g) from iPr₂O/heptane at ˜4° C. to give{7-ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne)ammonium(0.30 g) as a white solid. mp: 38-39° C. ¹H NMR (CDCl₃): δ=7.84 (d,J=8.4 Hz, 2H), 7.40 (d, J=7.8 Hz, 2H), 4.43 (dd, J=3.3, 10.8 Hz, 1H),4.10 (q, J=7.1 Hz, 2H), 2.48 (s, 3H), 2.23-2.12 (m, 1H), 1.90-1.77 (m,1H), 1.66-40 (m, 4H), 1.38-1.22 (m, 2H), 1.24 (t, J=7.1 Hz, 3H), 1.15(s, 6H). ¹³C NMR (CDCl₃): δ=177.3, 164.6, 146.3, 131.0, 129.93 (2×),129.87 (2×), 72.8, 60.4, 42.2, 40.2, 28.4, 26.0, 25.35, 25.30, 24.2,22.0, 14.5. Anal. calcd for C₁₉H₂₇NO₄S: C, 62.44; H, 7.45; N, 3.83.found: C, 62.57; H, 7.57; N, 3.96.

6.11 Tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate

Under an Ar atmosphere at 0° C., BuLi (2.5M in hexanes, 37 mL, 92.5mmol) was added drop wise to a solution of iPr₂NH (12.3 mL, 88 mmol,distilled from NaOH) in dry THF (150 mL) in 10 min. The reaction mixturewas stirred for 20 min, cooled to −70° C. and then, tert-butylcyclopropanecarboxylate (prepared according to Kohlrausch, K. W. F.;Skrabal, R., Z. Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285, 12.5g, 88 mmol) was added drop wise in 20 min. After 3 min,1-bromo-4-chlorobutane (13.7 mL, 20.1 g, 117 mmol) was added drop wisein 15 min. The reaction mixture was allowed to reach rt, poured into amixture of aqueous saturated NH₄Cl (200 mL) and ice (50 mL) andextracted with Et₂O (1×200 mL, 1×100 mL). The combined organic layerswere washed with brine, dried (Na₂SO₄) and evaporated in vacuo. Theremaining oil, was purified by fractional distillation to givetert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.73 g, 52%) asa colorless oil. bp: T=57-61° C. (p=0.001 mbar). ¹H NMR (CDCl₃): δ=3.52(t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H),1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd,J=6.6, 3.9 Hz, 2H). ¹³C NMR (CDCl₃): δ=173.9, 80.0, 45.1, 33.6, 32.9,28.2 (3×), 25.3, 24.2, 15.4 (2×). HRMS calcd for C₁₂H₂₂ClO₂ (MH⁺):233.1308. found: 233.1308.

6.12 Tert-butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate

To a solution of tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate(10.6 g, 45.7 mmol) in 2-butanone (50 mL) was added NaI (8.23 g, 54.5mmol). The reaction mixture was stirred under reflux overnight, dilutedwith Et₂O (100 mL), washed with a mixture of H₂O (100 mL) and aqueousNa₂S₂O₄ (0.5 M, 10 mL) and brine (50 mL). The organic phase was dried(Na₂SO₄) and evaporate in vacuo to give tert-butyl1-(4-iodobutyl)-1-cyclopropanecarboxylate (14.8 g, 94% pure by GC, 94%)as a slightly yellow liquid. ¹H NMR (CDCl₃): δ=3.18 (t, J=6.9 Hz, 2H),1.76 (quintet, J=7.1 Hz, 2H), 1.62-1.45 (m, 4H), 1.43 (s, 9H), 1.12 (dd,J=6.7 Hz, 3.8 Hz, 2H), 0.60 (dd, J=6.6 Hz, 3.9 Hz, 2H). ¹³C NMR (CDCl₃):δ=173.9, 80.0, 33.8, 33.3, 28.9, 28.2 (3×), 24.2, 15.5 (2×), 7.2. HRMScalcd for C₁₂H₂₁IO₂ (M⁺): 324.0587. found: 324.0587.

6.13 Ethyl11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate

Under a N₂ atmosphere at 0° C., a solution of{7-ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne)ammonium(20.5 g, 55.9 mmol) in N,N-dimethylacetamide (DMAc, 125 mL) followed bya solution of tert-butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate(18.11 g, 55.9 mmol) in DMAc (125 mL) were added drop wise in 30 and 20min, respectively to a solution of KOtBu (6.57 g, 58.7 mmol) in DMAc(250 mL). The mixture was allowed to reach rt and stirring was continuedfor 100 min. Then, the reaction mixture was quenched by the drop wiseaddition of H₂O (250 mL) while cooling with an ice-bath. The resultingmixture was extracted with Et₂O (3×250 mL) and the combined organiclayers were washed with brine (2×250 mL), dried (Na₂SO₄) and evaporatedin vacuo to give a yellow oil (31.79 g). Part of this oil (30.63 g) wasdissolved in CH₂Cl₂ (300 mL) and conc aqueous HCl (23 mL) was added.After 2 h of vigorous stirring, H₂O (250 mL) was added. The layers wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×250 mL).The combined organic phases were washed with saturated aqueous NaHCO₃(250 mL), dried (Na₂SO₄) and evaporated in vacuo. To the remainingsuspension of a yellow oil with a white solid was added heptane (˜50 mL)and the white solid was filtered off and washed with heptane (˜50 mL).The filtrate was stored at rt for 2 d and more white solid was formed,which was filtered off through a layer of silica (˜1 cm) and washed withheptane (˜50 mL). The combined filtrates were evaporated in vacuo togive impure ethyl11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate(17.90 g) as a colorless oil. This batch was further purified by columnchromatography (silica, heptane:EtOAc=40:1) to give ethyl11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate (9.83g, >90% pure by NMR, 43%) as a colorless oil. ¹H NMR (CDCl₃): δ=4.09 (q,J=7.2 Hz, 2H), 2.38 (t, J=7.2 Hz, 4H), 1.62-1.35 (m, 10H), 1.41 (s, 9H),1.26-1.17 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (s, 6H), 1.09 (dd,J=6.9, 4.2 Hz, 2H), 0.59 (dd, J=6.3, 3.6 Hz, 2H). ¹³C NMR: δ 210.5,177.4, 174.0, 79.8, 60.2, 42.8, 42.6, 42.1, 40.5, 34.0, 28.2 (3×), 27.5,25.2 (2×), 24.7, 24.3, 24.2, 24.1, 15.3 (2×), 14.4. HRMS calcd forC₂₃H₄₁O₅ (MH⁺): 397.2954. found: 397.2956.

6.14 11-(1-Carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid

A solution of ethyl11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate (9.27g, >90% pure by NMR, 21.0 mmol) in HCO₂H (50 mL) was stirred for 1.5 h,evaporated in vacuo and coevaporated from toluene (10 mL). The remainingresidue was dissolved in a mixture of EtOH and H₂O (2:1, 100 mL) andNaOH (5.33 g, 132 mmol) was added. The resulting clear solution waswarmed to 80° C. and after 5 h EtOH was evaporated in vacuo. Theremaining solution was diluted with H₂O to ˜100 mL, extracted with Et₂O(3×100 mL), acidified to pH ˜1 with cone aqueous HCl (˜9 mL) andextracted with Et₂O (3×100 mL). The latter organic layers were combined,dried (Na₂SO₄) and evaporated in vacuo. The remaining residue waspurified by column chromatography (silica, heptane:EtOAc=2:1 (containing1% (^(V)/_(V)) HOAc)) to give11-(1-carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid (5.83g, >90% pure by ¹H NMR, 80%) as a slightly yellow oil which turns solidwhen stored at −18° C. for several days. mp: 49-52° C. ¹H NMR (CD₃OD):δ=2.44 (t, J=7.2 Hz, 4H), 1.57-1.42 (m, 10H), 1.30-1.19 (m, 2H),1.17-1.07 (m, 2H), 1.14 (s, 6H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). ¹³C NMR(CD₃OD): δ=213.5, 181.4, 178.9, 43.5, 43.4, 43.0, 41.7, 34.9, 28.5, 25.9(3×), 25.5, 25.2, 24.3, 16.4 (2×). Anal. calcd for C₁₇H₂₈O₅: C, 65.36;H, 9.03. found: C, 65.06; H, 9.02.

6.15 11-(1-Carboxycyclopropyl)-7-hydroxy-2,2-dimethylundecanoic acid

To a mixture of 11-(1-carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoicacid (3.63 g, >90% pure by NMR, 10.4 mmol) in iPrOH (20 mL) and H₂O (20mL) was added NaOH (0.94 g, 23.5 mmol). After 5 min of stirring, NaBH₄(0.24 g, 6.3 mmol) was added to the resulting clear solution. After 19h, the mixture was acidified to pH˜1 with aqueous HCl (2M) and extractedwith Et₂O (3×50 mL). The combined organic phases were washed with brine(1×50 mL), dried (Na₂SO₄) and evaporated in vacuo. The remaining residuewas coevaporated in vacuo from EtOAc to give11-(1-carboxycyclopropyl)-7-hydroxy-2,2-dimethylundecanoic acid (3.43 g,93%, contains 8% (^(W)/_(W)) EtOAc and 3% (^(W)/_(W)) iPrOH) as aviscous colorless oil. ¹H NMR (CD₃OD): δ=3.5 (br s, 1H), 1.56-1.27 (m,16H), 1.16 (s, 6H), 1.16-1.14 (m, 2H), 0.72 (dd, J=3.4, 6.6 Hz, 2H). ¹³CNMR (CD₃OD): δ=181.6, 179.1, 72.3, 43.1, 42.0, 38.5, 38.4, 35.2, 29.0,27.5, 27.1, 26.4, 26.0, 25.9, 24.4, 16.43, 16.38. HRMS calcd forC₁₂H₃₁O₅ (M+H⁺): 315.2171. found 315.2175.

6.16 Ethyl 7-bromo-2,2-dimethylheptanoate

Under Ar atmosphere at −78° C., to a solution of ethyl isobutyrate(124.0 g, 1.06 mol) and DMPU (5 mL) in THF (160 mL) was added LDA (750mL, 2M). After 30 min, 1,5-dibromopentane (313 g, 1.32 mol) was added ina single portion. The reaction mixture was allowed to stir overnight,gradually warming to rt. The mixture was hydrolyzed with ice (500 g),saturated NH₄Cl (400 mL) and aqueous HCl (6M, 400 mL), and the solutionwas extracted with Et₂O (3×300 mL). The organic layers were washed withhalf saturated NaCl (2×300 mL), dried (MgSO₄) and evaporated in vacuo.The remaining residue was purified by distillation under reducedpressure to give ethyl 7-bromo-2,2-dimethylheptanoate (97.4 g, 32%) as acolorless oil. bp: T=109-110° C. (p=1.5-2 Torr). ¹H NMR (CDCl₃): δ=4.15(q, J=7.2 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.90-1.83 (m, 2H), 1.55-1.37(m, 4H), 1.25 (t, J=6.9 Hz, 3H), 1.30-1.22 (m, 2H), 1.16 (s, 6H). ¹³CNMR (CDCl₃): δ=177.9, 60.3, 42.2, 40.5, 33.7, 32.7, 28.6, 25.2, 24.2,14.3. HRMS calcd for C₁₁H₂₂BrO₂ (MH⁺): 265.0803. found: 265.0816.

6.17{8-Ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-xooctyl}(methylidyne)ammonium

Under a N₂ atmosphere, TosMIC (10.01 g, 51.3 mmol) and ethyl7-bromo-2,2-dimethylheptanoate (20.41 g, 77.0 mmol) were dissolved indry DMF (100 mL) and Bu₄NI (1.89 g, 5.12 mmol) and K₂CO₃ (10.62 g, 76.8mmol) were added while stirring vigorously. After 5 d, the reactionmixture was poured in an ice/H₂O mixture (500 mL), extracted with Et₂O(1×200 mL, 2×100 mL) The combined organic layers were washed with brine(2×50 mL), dried (Na₂SO₄), and evaporated in vacuo. The remainingresidue was purified by column chromatography (silica,heptane:EtOAc=3:1) to give in order of elution ethyl7-bromo-2,2-dimethylheptanoate (5.67 g, 90% pure by GC), an impure batchof{8-ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-oxooctyl}(methylidyne)ammonium(0.94 g), and pure{8-ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-oxooctyl}(methylidyne)ammonium(11.83 g, 61%) as a colorless oil. ¹H NMR (CDCl₃): δ=7.86 (d, J=8.1 Hz,2H), 7.43 (d, J=8.1 Hz, 2H), 4.45 (dd, J=10.9, 3.5 Hz, 1H), 4.11 (q,J=7.2 Hz, 2H), 2.49 (s, 3H), 2.22-2.11 (m, 1H), 1.90-1.77 (m, 1H),1.67-1.57 (m, 1H), 1.53-1.42 (m, 3H), 1.24 (t, J=7.2 Hz, 3H), 1.39-1.20(m, 4H), 1.15 (s, 6H). ¹³C NMR (CDCl₃): δ=177.8, 164.8, 146.5, 131.1,130.1 (2×), 130.0 (2×), 72.8, 60.2, 42.0, 40.3, 29.0, 28.3, 25.12, 25.06(2×), 24.5, 21.7, 14.2. HRMS calcd for C₂₀H₂₉NNaO₄S (MNa⁺): 402.1715.found: 402.1736.

6.18 Ethyl13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate

Under a N₂ atmosphere at 0° C., a solution of{8-ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-oxooctyl}(methylidyne)ammonium(28.4 g, 75.0 mmol) in N,N-dimethylacetamide (DMAc, 125 mL) followed bya solution of tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (B3,25.4 g, 75.0 mmol) in DMAc (125 mL) were added dropwise in 60 and 30min, respectively to a solution of KOtBu (8.83 g, 79.0 mmol) in DMAc(250 mL). The mixture was allowed to reach rt and stirring was continuedfor 2 h. Then, the reaction mixture was quenched by the dropwiseaddition of H₂O (250 mL) while cooling with an ice-bath. The resultingmixture was extracted with Et₂O (3×250 mL) and the combined organiclayers were washed with brine (2×250 mL), dried (Na₂SO₄) and evaporatedin vacuo to give a yellow oil (43.02 g). Part of this oil (42.50 g) wasdissolved in CH₂Cl₂ (250 mL) and conc aqueous HCl (34 mL) was added.After 1.5 h of vigorous stirring, H₂O (250 mL) was added. The layerswere separated and the aqueous phase was extracted with CH₂Cl₂ (3×250mL). The combined organic phases were washed with saturated aqueousNaHCO₃ (250 mL), dried (Na₂SO₄) and evaporated in vacuo. To theremaining residue was purified by column chromatography (silica,heptane:EtOAc=8:1) to give ethyl13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate(19.0 g, 95% pure by ¹H NMR, 57%) as a slightly yellow oil. ¹H NMR(CDCl₃): δ=4.09 (q, J=7.2 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.36 (t,J=7.2 Hz, 2H), 1.62-1.35 (m, 10H), 1.41 (s, 9H), 1.30-1.21 (m, 6H), 1.24(t, J=7.2 Hz, 3H), 1.14 (s, 6H), 1.09 (dd, J=6.6, 3.9 Hz, 2H), 0.58 (dd,J=6.3, 3.6 Hz, 2H). ¹³C NMR (CDCl₃): δ=210.8, 177.6, 174.1, 79.8, 60.2,42.9. 42.8, 42.2, 40.6, 34.1, 29.8, 29.6, 28.2 (3×), 27.6, 25.3 (2×),24.9, 24.3, 23.9, 23.8, 15.3 (2×), 14.4. HRMS calcd for C₂₅H₄₅O₅ (MH⁺):425.3267. found: 425.3267.

6.19 13-(1-Carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid

A solution of ethyl13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate(18.34 g, 43.3 mmol) in HCO₂H (50 mL) was stirred for 1.5 h, evaporatedin vacuo and coevaporated in vacuo from toluene (10 mL). The remainingresidue was dissolved in a mixture of EtOH and H₂O (2:1, 250 mL) andNaOH (9.68 g, 241 mmol) was added. The resulting clear solution waswarmed to 80° C. and after 5 h EtOH was evaporated in vacuo. Theremaining solution was diluted with H₂O to ˜250 mL, extracted with Et₂O(3×250 mL), acidified to pH ˜1 with conc aqueous HCl (˜18 mL) andextracted with Et₂O (3×250 mL). The latter organic layers were combined,dried (Na₂SO₄) and evaporated in vacuo to give a yellow oil whichsolidified overnight. The remaining residue was recrystallized fromiPr₂O/heptane to give13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (9.47 g,57%) as a white solid. The mother liquor was evaporated in vacuo and theremaining residue was purified by column chromatography(heptane:EtOAc=2:1 (containing 1% (^(V)/_(V)) HOAc)) andrecrystallization from iPr₂O/heptane to give a second batch13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (2.23 g,14%) as a white solid. mp=65-66° C. ¹H NMR: (CD₃OD): δ=2.43 (t, J=7.2Hz, 4H), 1.58-1.42 (m, 10H), 1.35-1.20 (m, 6H), 1.14 (s, 6H), 1.15-1.06(m, 2H), 0.70 (dd, J=6.6, 3.9 Hz, 2H). ¹³C NMR: (CD₃OD): δ=213.8, 181.6,179.0, 43.6, 43.5, 43.1, 41.9, 35.1, 31.0, 30.6, 28.7, 26.2, 25.9 (2×),25.02, 24.96, 24.4, 16.4 (2×). Anal. calcd for C₁₉H₃₂O₅: C, 67.03; H,9.47. found: C, 66.86; H, 9.50.

6.20 13-(1-Carboxycyclopropyl)-8-hydroxy-2,2-dimethyltridecanoic acid

To a mixture of 13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoicacid (3.67 g, 10.8 mmol) in iPrOH (20 mL) and H₂O (20 mL) was added NaOH(0.90 g, 22.5 mmol). After 5 min of stirring, NaBH₄ (0.20 g, 5.3 mmol)was added to the resulting clear solution. Additional NaBH₄ (0.10 g) wasadded after 100 min of stirring. After 16 h, the mixture was acidifiedto pH˜1 with aqueous HCl (1M) and extracted with Et₂O (3×50 mL). Thecombined organic phases were washed with brine (2×50 mL), dried(Na₂SO₄), evaporated in vacuo and coevaporated in vacuo from EtOAc (2×15mL) to give 1341-carboxycyclopropyl)-8-hydroxy-2,2-dimethyltridecanoicacid (3.99 g, 97%, contains 10% (^(W)/_(W)) EtOAc) as a viscouscolorless oil. ¹H NMR (CD₃OD): δ=3.48 (m, 1H), 1.50-1.21 (m, 20H), 1.14(s, 6H), 1.14-1.12 (m, 2H), 0.70 (dd, J=3.9, 6.3 Hz, 2H). ¹³C NMR(CD₃OD): δ=181.6, 179.0, 72.4, 43.2, 42.0, 38.6, 38.5, 35.2, 31.5, 31.2,28.9, 26.94, 26.87, 26.3, 25.94, 25.92, 24.4, 13.67, 16.36. HRMS calcdfor C₁₉H₃₅O₅ (M+H)⁺: 343.2484. found 343.2487.

6.21 Ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate

Under an N₂ atmosphere at ˜7° C., BuLi (2.5M in hexanes, 52.8 mL, 132mmol) was added drop wise to a solution of iPr₂NH (18.52 mL, 132 mmol,distilled from NaOH) in dry THF (70 mL) in 10 min. The reaction mixturewas allowed to warm to rt, stirred for 0.5 h, cooled to −60° C. andthen, ethyl 1-cyclobutanecarboxylate (prepared according to Török, B.;Molnár, Á., J. Chem. Soc. Perkin Trans. 1, 1993, 7, 801-804, 14.05 g,110 mmol) in dry THF (30 mL) was added dropwise in 20 min. The resultingmixture was allowed to warm to 0° C. in 20 min., cooled again to −60° C.and then, a solution of 1-bromo-4-chlorobutane (19.1 mL, 165 mmol) indry THF (30 mL) was added dropwise in 20 min, after which thetemperature was raised to −20° C. in 15 min. After 1.5 h, thetemperature was raised to −10° C. and stirring was continued for 1 h.The reaction mixture was allowed to reach rt, poured into a mixture ofaqueous saturated NH₄Cl (200 mL) and ice (50 mL) and extracted with Et₂O(500 mL). The organic layer was washed with brine (250 mL), dried(Na₂SO₄) and evaporated in vacuo. The remaining oil was purified byfractional distillation under reduced pressure to give ethyl1-(4-chlorobutyl)-1-cyclobutanecarboxylate (20.53 g, 86%) as a thin,colorless oil. ¹H NMR (CDCl₃): δ=4.13 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.8Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70 (m, 8H), 1.40-1.20 (m, 2H), 1.26(t, J=7.2 Hz, 3H). ¹³C NMR (CDCl₃): δ=176.6, 60.3, 47.6, 44.8, 37.3,32.8, 30.1 (2×), 22.4, 15.8, 14.4. HRMS calcd for C₁₁H₂₀(³⁷Cl)O₂ (MH⁺):221.1122. found: 221.1116.

6.22 Ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate

To a solution of ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (21.21g, 97.0 mmol) in 2-butanone (125 mL) was added NaI (19.07 g, 127 mmol).The reaction mixture was stirred under reflux for 20 h and diluted withEt₂O (500 mL). The resulting mixture was washed with aqueous Na₂S₂O₃(10% (^(W)/_(W)), 250 mL), brine (250 mL), dried (Na₂SO₄) and evaporatedin vacuo to give ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (29.91g, 99%) as a slightly yellow oil. ¹H NMR (CDCl₃): δ=4.14 (q, J=7.1 Hz,2H), 3.17 (t, J=6.9 Hz, 2H), 2.49-2.32 (m, 2H), 1.98-1.69 (m, 8H),1.37-1.19 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). ¹³C NMR (CDCl₃): δ=176.5,60.3, 47.5, 36.9, 33.7, 30.1 (2×), 26.0, 15.7, 14.5, 6.8. HRMS calcd forC₁₁H₂₀IO₂ (MH⁺): 311.0508. found: 311.0511.

6.23 Ethyl1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate

Under a N₂ atmosphere at 0° C., KOtBu (8.61 g, 76.7 mmol) was addedportion wise to a solution of ethyl1-(4-iodobutyl)-1-cyclobutanecarboxylate (24.83 g, 80.1 mmol) and TosMIC(7.26 g, 36.4 mmol) in DMAc (150 mL). After 30 min, the reaction mixturewas allowed to warm to rt, stirred for 1.5 h and diluted with DMAc (10mL). Then, ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (2.01 g, 6.5mmol) and KOtBu (0.81 g, 7.2 mmol) were added followed by anotherportion of ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (1.00 g, 3.2mmol) and KOtBu (0.86 g, 7.7 mmol) after 1 h. After 1 h, the reactionmixture was poured into a mixture of Et₂O (700 mL) and aqueous NaCl(10%, 500 mL) and the layers were separated. The organic layer waswashed with brine (1×500 mL, 1×300 mL), dried (Na₂SO₄) and evaporated invacuo. The remaining residue was purified by column chromatography(silica, heptane:EtOAc=6:1) to give ethyl1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl-1-cyclobutanecarboxylate(18.35 g) as a slightly yellow oil. Part of this oil (15.62 g, 27.9mmol) was dissolved in CH₂Cl₂ (200 mL) and conc aqueous HCl (75 mL) wasadded. After stirring vigorously for 2 h, H₂O (300 mL) was added and thelayers were separated. The aqueous layer was extracted with CH₂Cl₂(2×100 mL) and the combined CH₂Cl₂ layers were washed with saturatedaqueous NaHCO₃ (2×250 mL) and brine (250 mL). All aqueous layers werecombined and extracted with Et₂O (2×200 mL). The combined Et₂O layerswere washed with saturated aqueous NaHCO₃ (200 mL) and brine (200 mL).The CH₂Cl₂ layers and Et₂O layers were combined, dried (Na₂SO₄) andevaporated in vacuo. To the remaining residue heptane (150 mL) wasadded, and the mixture was filtered through two stacked folded filterpapers. The hazy filtrate was filtered again to give a clear filtrate,which was evaporated in vacuo. The remaining residue was purified bycolumn chromatography (silica, heptane:EtOAc=6:1) to give ethyl1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate(9.99 g, 82%) as a slightly yellow liquid, after evaporation from CH₂Cl₂(100 mL). ¹H NMR (CDCl₃): δ=4.12 (q, J=7.1 Hz, 4H), 2.44-2.32 (m, 8H),1.93-1.79 (m, 8H), 1.77-1.72 (m, 4H), 1.55 (quintet, J=7.5 Hz, 4H), 1.25(t, J=7.1 Hz, 6H), 1.21-1.10 (m, 4H). ¹³C NMR (CDCl₃): δ=210.2, 176.7(2×), 60.2 (2×), 47.6 (2×), 42.6 (2×), 37.9 (2×), 30.1 (4×), 24.7 (2×),24.1 (2×), 15.7 (2×), 14.4 (2×). HRMS calcd for C₂₃H₃₈O₅ (M⁺): 394.2719.found: 394.2703.

6.24 1-[9-(1-Carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylicacid

LiOH.H₂O (3.94 g, 93.9 mmol) and H₂O (30 mL) were added to a solution ofethyl1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate(9.20 g, 23.3 mmol) in EtOH (90 mL) and the resulting mixture wasstirred at reflux temperature for 17 h, allowed to cool to rt andconcentrated in vacuo to a smaller volume. H₂O (150 mL) was added andthe resulting mixture was extracted with Et₂O (50 mL), acidified withaqueous HCl (6 M, 25 mL) and extracted with Et₂O (1×100 mL, 2×50 mL).The latter organic layers were combined, washed with brine (50 mL),dried (Na₂SO₄) and evaporated in vacuo. The remaining residue wasrecrystallized from a mixture of iPr₂O and heptane to give1-[9-(1-carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic acid(4.41 g, 56%) as small, white granules. mp 69-70° C. ¹H NMR (CDCl₃):δ=11.2 (br s, 2H), 2.50-2.37 (m, 4H), 2.39 (t, J=7.2 Hz, 4H), 1.96-1.84(m, 8H), 1.81-1.75 (m, 4H), 1.57 (quintet, J=7.4 Hz, 4H), 1.26-1.12 (m,4H). ¹³C NMR (CDCl₃): δ=210.6, 183.4 (2×), 47.6 (2×), 42.7 (2×), 37.8(2×), 30.1 (4×). 24.7 (2×), 24.1 (2×), 15.7 (2×). Anal. calcd forC₁₉H₃₀O₅: C, 67.43; H, 8.93. found: C, 67.19; H, 8.97.

6.25 1-[9-(1-Carboxycyclobutyl)-5-hydroxynonyl]-1-cyclobutanecarboxylicacid

To a solution of1-[9-(1-carboxycyclobutyl)-5-oxononyl]-1-cyclobutanecarboxylic acid(7.83 g, 23.1 mmol) in aqueous NaOH (1M, 70 mL) and i-PrOH (70 mL) wasadded NaBH₄ (0.659 g, 17.3 mmol). After stirring for 3.5 h, the reactionmixture was acidified to pH˜1 with conc HCl and extracted with Et₂O(1×250 mL, 2×150 mL). The combined organic layers were washed with brine(250 mL), dried (Na₂SO₄) and concentrated in vacuo. The remainingresidue was dried under high vacuum to give1-[9-(1-carboxycyclobutyl)-5-hydroxynonyl]-1-cyclobutanecarboxylic acid(8.17 g, 97%, contains 7% (^(W)/_(W)) Et₂O) as a thick, colorless oil.¹H NMR (CDCl₃): δ=8.56 (br s, 3H), 3.58 (br s, 1H), 2.55-2.30 (m, 4H),2.00-1.80 (m, 8H), 1.78 (t, J=7.7 Hz, 4H), 1.52-1.15 (m, 12H). ¹³C NMR(CDCl₃): δ=183.0 (2×), 71.7, 47.7 (2×), 38.0 (2×), 37.1 (2×), 30.2 (2×),30.1 (2×), 25.9 (2×), 25.0 (2×), 15.7 (2×).

6.26 Butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate

Under a N₂ atmosphere at −60° C., a solution of butylcyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C.W., J. Org. Chem., 1957, 22, 1680-1682, 80.0 g, 0.42 mol) and1,4-dibromobutane (183.3 g, 0.84 mol) in dry THF (700 mL) was added dropwise to a mixture of LDA (2M in THF/heptane/ethylbenzene, 250 mL, 0.50mol) and dry THF (250 mL) in 1.5 h. After that, the reaction mixture wasallowed to slowly reach rt during 3.5 h. Then, the reaction mixture waspoured into ice-cold saturated aqueous NH₄Cl (1 L). The organic layerwas decanted and concentrated in vacuo to a smaller volume. The aqueouslayer was extracted with Et₂O (3×250 mL). The combined organic layerswere washed with saturated aqueous NH₄Cl (250 mL) and brine (2×250 mL),dried (Na₂SO₄) and evaporated in vacuo. The remaining residue waspurified by fractional distillation to give butyl1-(4-bromo-butyl)-cyclopentanecarboxylate (62.8 g, 49%) as a lightyellow liquid. bp: T=116-117° C. (p=0.040-0.051 Torr). ¹H NMR (CDCl₃):δ=4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H),1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94(t, J=7.2 Hz, 3H). ¹³C NMR (CDCl₃): δ=177.6, 64.1, 53.9, 38.2, 36.0(2×), 33.3, 33.0, 30.6, 24.8 (2×), 24.6, 19.1, 13.6. HRMS calcd forC₁₄H₂₅BrO₂ (M⁺): 304.1038. found: 304.1042.

6.27 Butyl1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate

Under a N₂ atmosphere, NaH (60% (^(W)/_(W)) in mineral oil, 3.20 g, 80.0mmol) was added portion wise to a solution of TosMIC (6.58 g, 33.0 mmol)and Bu₄NI (1.31 g, 3.55 mmol) in dry DMSO (100 mL) while stirringvigorously and cooling with a water bath. After 30 min, butyl1-(4-bromo-butyl)-cyclopentanecarboxylate (21.59 g, 67.2 mmol) was addeddrop wise to the mixture in 20 min and after 1 h of stirring, anotherportion of NaH (60% (^(W)/_(W)) in mineral oil, 0.56 g, 14 mmol) wasadded. After 20 min, H₂O (250 mL, ice-cold) was added drop wise whilecooling with a water bath and the resulting mixture was extracted withEt₂O (3×100 mL). The combined organic layers were washed with brine(2×100 mL), dried (Na₂SO₄) and filtered through a layer of silica. Theresidue was washed with Et₂O (200 mL) and the combined filtrate andwashings were evaporated in vacuo. The remaining oil was purified bycolumn chromatography (silica, heptane/EtOAc=8:1) to give butyl1-{9-[1-(butoxycarbonyl)cyclopentyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl}-1-cyclopentanecarboxylateas a yellow oil (13.38 g). This oil (13.38 g) was dissolved in CH₂Cl₂(250 mL), and conc aqueous HCl (75 mL) was added. After stirringvigorously for 18 h, H₂O (300 mL) was added and the layers wereseparated. The aqueous phase was extracted with CH₂Cl₂ (2×100 mL) andthe combined organic layers were washed with saturated aqueous NaHCO₃(2×250 mL) and brine (250 mL), dried (Na₂SO₄) and evaporated in vacuo.The remaining residue was suspended in heptane (100 mL) and filtered.The filtrate was evaporated in vacuo. The remaining residue was purifiedby column chromatography (silica, heptane/EtOAc=6:1) to give butyl1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate(9.05 g, 56%) as a slightly yellow liquid. ¹H NMR (CDCl₃): δ=4.05 (t,J=6.5 Hz, 4H), 2.36 (t, J=7.5 Hz, 4H), 2.14-2.05 (m, 4H), 1.65-1.32 (m,28H), 1.24-1.16 (m, 4H), 0.96 (t, J=7.2 Hz, 6H). ¹³C NMR (CDCl₃):δ=210.8, 177.8 (2×), 64.1 (2×), 54.0 (2×), 42.6 (2×), 39.0 (2×), 36.0(4×), 30.7 (2×), 25.6 (2×), 24.9 (4×), 24.1 (2×), 19.1 (2×), 13.6 (2×).HRMS calcd for C₂₉H₅₀O₅ (M⁺): 478.3658. found 478.3663.

6.28 1-[9-(1-Carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylicacid

LiOH.H₂O (3.21 g, 76.4 mmol) and H₂O (40 mL) were added to a solution ofbutyl1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate(7.25 g, 15.0 mmol) in EtOH (120 mL) and the resulting mixture wasstirred at reflux temperature for 25 h, allowed to cool to rt andconcentrated in vacuo to a smaller volume. H₂O (100 mL) was added andthe resulting mixture was extracted with Et₂O (25 mL), acidified withaqueous HCl (6 M, 15 mL) and extracted with Et₂O (3×50 mL). The latterorganic layers were combined, dried (Na₂SO₄, to avoid loss of material,a minimal amount of Na₂SO₄ was used, with the desiccant becoming awhite, oily paste. The organic layer was decanted from the desiccant.)and evaporated in vacuo to give1-[9-(1-carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid(5.46 g, 95% pure by ¹H NMR, 94%, mp=99-103° C.) as a white solid. Ananalytical sample was obtained after recrystallization fromiPr₂O/heptane. mp=104-106° C. ¹H NMR (CDCl₃): δ=2.39 (t, J=6.9 Hz, 4H),2.18-2.10 (m, 4H), 1.69-141 (m, 20H), 1.27-1.14 (m, 4H). ¹³C NMR(CDCl₃): δ=211.1, 184.6 (2×), 53.9 (2×), 42.5 (2×), 39.0 (2×), 35.9(4×), 25.7 (2×), 24.9 (4×), 24.0 (2×). Anal. calcd for C₂₁H₃₄O₅: C,68.82; H, 9.35. found: C, 68.78; H, 9.47.

6.291-[9-(1-Carboxycyclopentyl)-5-hydroxynonyl]-1-cyclo-pentanecarboxylicacid

To a mixture of1-[9-(1-carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid(4.70 g, 11.5 mmol) in iPrOH (30 mL) and H₂O (30 mL) was added NaOH(1.10 g, 27 mmol). To the resulting clear solution, NaBH₄ (0.242 g, 6.4mmol) was added. After 23 h, TLC analysis revealed the reaction to beincomplete, and an additional portion of NaBH₄ (0.036 g, 0.95 mmol) wasadded. Stirring was continued for 17 h and then, the reaction mixturewas concentrated in vacuo. The remaining residue was dissolved in H₂O(80 mL) and washed with Et₂O (20 mL). The aqueous layer was acidifiedwith aqueous HCl (6M, 15 mL) and then extracted with Et₂O (3×50 mL). Thecombined organic layers were washed with brine (2×50 mL), dried (Na₂SO₄)and concentrated in vacuo to give1-[9-(1-carboxycyclopentyl)-5-hydroxynonyl]-1-cyclo-pentanecarboxylicacid (4.45 g, 98%, contains 7% (%) Et₂O) as a thick, slightly hazy,light yellow oil. ¹H NMR (CDCl₃): δ=3.56 (br s, 1H), 2.16-2.10 (m, 4H),1.65-1.60 (m, 12H), 1.51-1.18 (m, 16H). ¹³C NMR (CDCl₃): δ=184.1 (2×),71.1, 54.2 (2×), 39.4 (2×), 37.1 (2×), 36.1 (2×), 35.7 (2×), 26.0 (2×),25.8 (2×), 25.03 (2×), 25.00 (2×).

6.30 Butyl 1-(5-bromo-pentyl)-cyclopentanecarboxylate

Under a N₂ atmosphere at −60° C., a solution of butylcyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C.W., J. Org. Chem., 1957, 22, 1680-1682, 40.2 g, 0.236 mol) and1,5-dibromopentane (64 mL, 0.45 mol) in dry THF (400 mL) was added dropwise to a solution of LDA (2M in THF/heptane/ethylbenzene, 200 mL, 0.40mol) in 30 min. After 3 h, the reaction mixture was allowed to reach rtin 30 min. Then the reaction mixture was poured out into ice-coldsaturated aqueous NH₄Cl (1 L). The organic layer was decanted andconcentrated in vacuo to a smaller volume. The aqueous layer wasextracted with Et₂O (3×150 mL). The combined organic layers were washedwith saturated aqueous NH₄Cl (3×150 mL), brine (150 mL), dried (Na₂SO₄)and evaporated in vacuo. The remaining residue was purified byfractional distillation to give butyl1-(5-bromo-pentyl)-cyclopentanecarboxylate (49.1 g, >90% pure by GC,59%) as a bright yellow liquid. bp: T=123° C. (p=0.001 Torr). ¹H NMR(CDCl₃): δ=4.06 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.9 Hz, 2H), 2.15-2.07 (m,2H), 1.89-1.79 (quintet, J=7.1 Hz, 2H), 1.69-1.56 (m, 8H), 1.49-1.32 (m,6H), 1.28-1.17 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). ¹³C NMR (CDCl₃):δ=177.7, 64.0, 54.0, 39.0, 36.0 (2×), 33.6, 32.5, 30.7, 28.5, 25.1, 24.8(2×), 19.1, 13.6. HRMS calcd for C₁₅H₂₇BrO₂ (M⁺): 318.1195. found:318.1192.

6.31 Butyl1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate

Under a N₂ atmosphere, NaH (60% (^(W)/_(W)) in mineral oil, 7.55 g, 189mmol) was added portion wise to a solution of TosMIC (12.48 g, 62.6mmol) and Bu₄NI (2.56 g, 6.93 mmol) in dry DMSO (200 mL) while stirringvigorously and cooling with a water bath. After 30 min, butyl1-(5-bromo-pentyl)-cyclopentanecarboxylate (44.46 g, >90% pure by GC,125 mmol) was added drop wise to the mixture in 20 min and after 1 h ofstirring, another portion of NaH (60% (^(W)/_(W)) in mineral oil, 1.20g, 30.0 mmol) was added. After 1 h, the reaction mixture was slowlypoured into ice-cold H₂O (500 mL) and the resulting mixture wasextracted with Et₂O (3×250 mL). The combined organic layers were washedwith aqueous NaCl (10%, 250 mL) and brine (2×200 mL), dried (Na₂SO₄) andfiltered through a layer of silica (150 g). The residue was washed withEt₂O (250 mL) and the combined filtrate and washings were evaporated invacuo. The remaining oil was purified by column chromatography (silica,heptane:EtOAc=8:1) to give butyl1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-isocyano-6-[(4-methylphenyl)sulfonyl]undecyl}-1-cyclopentanecarboxylateas a yellow oil (32.79 g). This oil (32.79 g) was dissolved in CH₂Cl₂(400 mL), and conc aqueous HCl (150 mL) was added. After stirringvigorously for 4.5 h, H₂O (500 mL) was added and the layers wereseparated. The aqueous phase was extracted with CH₂Cl₂ (2×100 mL) andthe combined organic layers were washed with saturated H₂O (200 mL),saturated aqueous NaHCO₃ (500 mL) and brine (500 mL), dried (Na₂SO₄) andevaporated in vacuo. The remaining residue was purified by columnchromatography (silica, heptane:EtOAc=6:1) to give butyl1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate(24.11 g, 90% pure by ¹H NMR, 69%) as a slightly yellow liquid. ¹H NMR(CDCl₃): δ=4.06 (t, J=6.6 Hz, 4H), 2.36 (t, J=7.4 Hz, 4H), 2.15-2.06 (m,4H), 1.65-1.52 (m, 20H), 1.49-1.32 (m, 8H), 1.27-1.19 (m, 8H), 0.94 (t,J=7.4 Hz, 6H). ¹³C NMR (CDCl₃): δ=210.9, 177.6 (2×), 63.8 (2×), 54.0(2×), 42.5 (2×), 38.9 (2×), 35.8 (4×), 30.6 (2×), 29.5 (2×), 25.6 (2×),24.7 (4×), 23.4 (2×), 19.0 (2×), 13.5 (2×). FIRMS calcd for C₃₁H₅₄O₅(M⁺): 506.3971. found: 506.3981.

6.32 1-[11-(1-Carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylicacid

LiOH.H₂O (7.83 g, 187 mmol) and H₂O (100 mL) were added to a solution ofbutyl1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate(21.03 g, 90% pure by ¹H NMR, 37.3 mmol) in EtOH (300 mL) and theresulting mixture was stirred at reflux temperature for 2 d, allowed tocool to rt and concentrated in vacuo to a smaller volume. H₂O (100 mL)was added and the resulting mixture was extracted with Et₂O (100 mL),acidified with conc aqueous HCl (25 mL) and extracted with Et₂O (3×150mL). The latter organic layers were combined, dried (Na₂SO₄; To avoidloss of material, a minimal amount of Na₂SO₄ was used, with thedesiccant becoming a white, oily paste. The organic layer was decantedfrom the desiccant.) and evaporated in vacuo. The remaining residue waspurified by recrystallization from a mixture of iPr₂O and heptane togive 1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylicacid (12.15 g, 83%) as white granules. mp=78-85° C. ¹H NMR (CDCl₃):δ=2.37 (t, J=7.4 Hz, 4H), 2.18-2.10 (m, 4H), 1.65-1.45 (m, 20H),1.29-1.25 (m, 8H). ¹³C NMR (CDCl₃): δ=211.5, 184.8 (2×), 54.0 (2×), 42.4(2×), 38.9 (2×), 35.9 (4×), 29.2 (2×), 25.5 (2×), 24.9 (4×), 23.5 (2×).Anal. calcd for C₂₃H₃₈O₅: C, 70.02; H, 9.71. found: C, 70.37; H, 9.72.

6.331-[11-(1-Carboxycyclopentyl)-6-hydroxyundecyl]-1-cyclopentanecarboxylicacid

To a mixture of1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid(5.00 g, 12.7 mmol) in iPrOH (30 mL) and H₂O (30 mL) was added NaOH(1.07 g, 26.3 mmol). To the resulting clear solution, NaBH₄ (0.38 g,10.0 mmol) was added. After 19 h, the reaction mixture was concentratedin vacuo. The remaining residue was dissolved in H₂O (50 mL) andacidified with aqueous HCl (6M, 15 mL). The resulting mixture wasextracted with Et₂O (100 mL, 2×50 mL), and the combined organic layerswere washed with brine (2×50 mL), dried (Na₂SO₄) and concentrated invacuo to give1-[11-(1-carboxycyclopentyl)-6-hydroxyundecyl]-1-cyclopentanecarboxylicacid (5.18 g, 99%, contains 4% (%) Et₂O) as a thick, light yellow oilthat slowly crystallized on standing. mp=: 76-77° C. ¹H NMR (CDCl₃);δ=3.56 (br s, 1H), 2.16-2.11 (m, 4H), 1.64-1.61 (m, 12H), 1.51-1.18 (m,20H). ¹³C NMR (CDCl₃): δ=184.3 (2×), 71.4, 54.2 (2×), 39.2 (2×), 36.9(2×), 36.2 (2×), 35.7 (2×), 29.5 (2×), 25.9 (2×), 25.2 (2×), 25.1 (2×),25.0 (2×).

7. BIOLOGICAL ASSAYS 7.1 Effects of Illustrative Compounds of theInvention on NonHDL Cholesterol, HDL Cholesterol, Triglyceride Levels,Glycemic Control Indicators and Body Weight Control in Obese FemaleZucker Rats

In a number of different experiments, illustrative compounds of theinvention are administered daily at a dose of up to 100 mg/kg to chowfed obese female Zucker rats for fourteen days in the morning by oralgavage in 1.5% carboxymethylcellulose/0.2% Tween 20 or 20% ethanol/80%polyethylene glycol (dosing vehicles). Animals are weighed daily.Animals are allowed free access to rodent chow and water throughout thestudy except on days of blood sampling where food is restricted for sixhours prior to blood sampling. Blood glucose is determined after the 6hour fast in the afternoon without anesthesia from a tail vein. Serum isalso prepared from pretreatment blood samples subsequently obtained fromthe orbital venous plexus (with O₂/CO₂ anesthesia) and following thefourteenth dose at sacrifice from the heart following O₂/CO₂ anesthesia.Serums are assayed for lipoprotein cholesterol profiles, triglycerides,total cholesterol, Non-HDL cholesterol, HDL cholesterol, the ratio ofHDL cholesterol to that of Non-HDL cholesterol, insulin, non-esterifiedfatty acids, and beta-hydroxy butyric acid. The percent body weight gainand the ratio of liver to body weight is also determined. These areshown as absolute values or as a percent change of the pretreatmentvalues in Table 1.

TABLE 1 Examples of effects of oral daily treatment of obese femaleZucker rats with illustrative compounds of the invention for fourteendays Percent of Pre-treatment Expt. Dose % wt. HDL-C/ Non- Compound # n(mg/kg/day) gain non-HDL-C TG TC HDL-C HDL-C Glucose Insulin NEFA BHAVehicle LR132 4 30 10.50% 4 3 5 −8 10 −2 42 −3 78 A 4 12.3 4 −23 37 −2076 −1 −8 −30 150 Vehicle LR132 4 100 10.5 4 3 5 −8 10 −2 42 −3 78 B 44.2 153 −91 13 −94 54 −24 −51 −23 254 Vehicle LR132 4 100 10.5 4 3 5 −810 −2 42 −3 78 D 4 −1.7 785 −97 −11 −98 15 −13 −70 −44 195 Vehicle LR1324 100 10.5 4 3 5 −8 10 −2 42 −3 78 E 3 10.4 5 −34 101 1 162 −2 2 −24 223n is number of animals per experiment

7.2 Effects of Illustrative Compounds of the Invention on the In VitroLipid Synthesis in Isolated Hepatocytes

Compounds were tested for inhibition of lipid synthesis in primarycultures of rat hepatocytes. Male Sprague-Dawley rats were anesthetizedwith intraperitoneal injection of sodium pentobarbital (80 mg/kg). Rathepatocytes were isolated essentially as described by the method ofSeglen (Seglen, P. O. Hepatocyte suspensions and cultures as tools inexperimental carcinogenesis. J. Toxicol. Environ. Health 1979, 5,551-560). Hepatocytes were suspended in Dulbecco's Modified EaglesMedium containing 25 mM D-glucose, 14 mM HEPES, 5 mM L-glutamine, 5 mMleucine, 5 mM alanine, 10 mM lactate, 1 mM pyruvate, 0.2% bovine serumalbumin, 17.4 mM non-essential amino acids, 20% fetal bovine serum, 100nM insulin and 20 μg/mL gentamycin) and plated at a density of 1.5×10⁵cells/cm² on collagen-coated 96-well plates. Four hours after plating,media was replaced with the same media without serum. Cells were grownovernight to allow formation of monolayer cultures. Lipid synthesisincubation conditions were initially assessed to ensure the linearity of[1-¹⁴C]-acetate incorporation into hepatocyte lipids for up to 4 hours.Hepatocyte lipid synthesis inhibitory activity was assessed duringincubations in the presence of 0.25 μCi [1-¹⁴C]-acetate/well (finalradiospecific activity in assay is 1 Ci/mol) and 0, 1, 3, 10, 30, 100 or300 μM of compounds for 4 hours. At the end of the 4-hour incubationperiod, medium was discarded and cells were washed twice with ice-coldphosphate buffered saline and stored frozen prior to analysis. Todetermine total lipid synthesis, 170 μl of MicroScint-E® and 50 μl waterwas added to each well to extract and partition the lipid solubleproducts to the upper organic phase containing the scintillant. Lipidradioactivity was assessed by scintillation spectroscopy in a PackardTopCount NXT. Lipid synthesis rates were used to determine the IC₅₀s ofthe compounds that are presented in Table 2.

TABLE 2 Effect of Illustrative Compounds A, B, and D-F on LipidSynthesis in Primary Rat Hepatocytes. 95% Confidence Interval CompoundIC₅₀ (μM) Lower Upper r² A 12.0 5.4 26.3  0.98 B  0.9 0.8 1.1 0.99 D 1.4 1.2 1.6 0.99 E  3.0 2.6 3.4 0.98 F  1.8 1.4 2.3 0.96

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodimentswhich are functionally equivalent are within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art and are intended to fall within the appended claims.

What is claimed is:
 1. A method for treating or preventing acardiovascular disease in a patient, comprising administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt, hydrate, solvate or a mixturethereof, wherein: (a) each occurrence of m is independently an integerranging from 0 to 5; (b) each occurrence of n is independently aninteger ranging from 3 to 7; (c) X is (CH₂)_(z) or Ph; wherein z is aninteger from 0 to 4; (d) each occurrence of R¹ and R² is independently(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, benzyl, or R¹ andR² and the carbon to which they are both attached are taken together toform a (C₃-C₇)cycloakyl group; (e) each occurrence of R¹¹ and R¹² andthe carbon to which they are both attached are taken together to form a(C₃-C₇)cycloakyl group; (f) each occurrence of Y¹ and Y² isindependently (C₁-C₆)alkyl, OH, COOH, COOR³, SO₃H,

wherein: (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁-C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁴ isindependently H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁-C₆ alkoxy, orphenyl groups; and (iii) each occurrence of R⁵ is independently H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.
 2. The method of claim1, wherein each occurrence of Y¹ and Y² is independently OH, COOR³, orCOOH.
 3. The method of claim 1, wherein m is
 0. 4. The method of claim1, wherein m is
 1. 5. The method of claim 1, wherein n is
 4. 6. Themethod of claim 1, wherein n is
 5. 7. The method of claim 1, wherein Xis (CH₂)_(z) and z is
 0. 8. The method of claim 1, wherein eachoccurrence of R¹ and R² and the carbon to which they are both attachedare taken together to form a (C₃-C₇)cycloakyl group.
 9. The method ofclaim 1, wherein Y¹ and Y² are each independently (C₁-C₆)alkyl.
 10. Themethod of claim 1, wherein Y¹ and Y² are each methyl.
 11. A method ofincreasing HDL levels, which comprises administering to a patient inneed thereof a therapeutically effective amount of a compound of formulaI:

or a pharmaceutically acceptable salt, hydrate, solvate or a mixturethereof, wherein: (a) each occurrence of m is independently an integerranging from 0 to 5; (b) each occurrence of n is independently aninteger ranging from 3 to 7; (c) X is (CH₂)_(Z) or Ph; wherein z is aninteger from 0 to 4; (d) each occurrence of R¹ and R² is independently(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, benzyl, or R¹ andR² and the carbon to which they are both attached are taken to form a(C₃-C₇)cycloakyl group; (e) each occurrence of R¹¹ and R¹² and thecarbon to which they are both attached are taken together to form a(C₃-C₇)cycloakyl group; (f) each occurrence of Y¹ and Y² isindependently (C₁-C₆)alkyl, OH, COOH, COOR³, SO₃H,

wherein: (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkynyl, phenyl, or benzyl andis unsubstituted or substituted with one or more halo, OH,(C₁-C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁴ isindependently H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁-C₆ alkoxy, orphenyl groups; and (iii) each occurrence of R⁵ is independently H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.
 12. A method ofdecreasing LDL levels, which comprises administering to a patient inneed thereof a therapeutically effective amount of a compound of formulaI:

or a pharmaceutically acceptable salt, hydrate, solvate or a mixturethereof, wherein: (a) each occurrence of m is independently an integerranging from 0 to 5; (b) each occurrence of n is independently aninteger ranging from 3 to 7; (c) X is (CH₂)_(Z) or Ph; wherein z is aninteger from 0 to 4; (d) each occurrence of R¹ and R² is independently(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, benzyl, or R¹ andR² and the carbon to which they are both attached are taken together toform a (C₃-C₇)cycloakyl group; (e) each occurrence of R¹¹ and R¹² andthe carbon to which they are both attached are taken together to form a(C₃-C₇)cycloakyl group; (f) each occurrence of Y¹ and Y² is independent(C₁-C₆)alkyl, OH, COOH, COOR³, SO₃H,

wherein: (i) R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁-C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁴ isindependently H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁-C₆ alkoxy, orphenyl groups; and (iii) each occurrence of R⁵ is independently H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl.
 13. A method accordingto claim 1 wherein the compound of formula I is selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 14. A method according toclaim 11 wherein the compound of formula I is selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 15. A method according toclaim 12 wherein the compound of formula I is selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 16. A method according toclaim 1 wherein the compound is represented by the formula

or a pharmaceutically acceptable salt thereof.
 17. A method according toclaim 1 wherein the compound is represented by the formula

or a pharmaceutically acceptable salt thereof.
 18. A method according toclaim 1 wherein the compound is represented by the formula

or a pharmaceutically acceptable salt thereof.
 19. A method according toclaim 1 wherein the compound is represented by the formula

or a pharmaceutically acceptable salt thereof.
 20. A method according toclaim 12 wherein the compound is represented by the formula

or a pharmaceutically acceptable salt thereof.
 21. A method according toclaim 12 wherein the compound is represented by the formula

or a pharmaceutically acceptable salt thereof.
 22. A method according toclaim 12 wherein the compound is represented by the formula

or a pharmaceutically acceptable salt thereof.
 23. A method according toclaim 12 wherein the compound is represented by the formula

or a pharmaceutically acceptable salt thereof.